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Review Article

MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present)

Author(s): Rafał Rusiecki, Jakub Witkowski* and Joanna Jaszczewska-Adamczak

Volume 14, Issue 4, 2019

Page: [324 - 369] Pages: 46

DOI: 10.2174/1574892814666191022163540

Price: $65

Abstract

Background: Mouse Double Minute 2 protein (MDM2) is a cellular regulator of p53 tumor suppressor (p53). Inhibition of the interaction between MDM2 and p53 proteins is a promising anticancer therapy.

Objective: This updated patent review is an attempt to compile the research and achievements of the various researchers working on small molecule MDM2 inhibitors from 2010 to date. We provide an outlook into the future for therapy based on MDM2 inhibition by presenting an overview of the most relevant patents which have recently appeared in the literature.

Methods: Literature and recent patents focusing on the anticancer potential of MDM2-p53 interaction inhibitors and its applications have been analyzed. We put the main emphasis on the most perspective compounds which are or were examined in clinical trials.

Results: Literature data indicated that MDM2 inhibitors are therapeutically effective in specific types of cancer or non-cancer diseases. A great number of patents and research work around new MDM2- p53 interaction inhibitors, possible combinations, new indications, clinical regimens in previous years prove that this targeted therapy is in the scope of interest for many business and academic research groups.

Conclusion: Novel MDM2 inhibitors thanks to higher potency and better ADME properties have shown effectiveness in preclinical and clinical development however the final improvement of therapeutic potential for MDM2 inhibitors might depend on the useful combination therapy and exploring new cancer and non-cancer indications.

Keywords: Anticancer, combination therapy, LAG3, MDM2 inhibitor, molecular targeted therapy, p53, patent, PD-1.

« Previous Next »
[1]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69(1): 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402]
[3]
Wartman LD. The future of cancer treatment using precision oncogenomics. Cold Spring Harb Mol Case Stud 2018; 4(2)a002824
[http://dx.doi.org/10.1101/mcs.a002824] [PMID: 29610395]
[4]
Di Cintio A, Di Gennaro E, Budillon A. Restoring p53 function in cancer: Novel therapeutic approaches for applying the brakes to tumorigenesis. Recent Patents Anticancer Drug Discov 2010; 5(1): 1-13.
[http://dx.doi.org/10.2174/157489210789702172] [PMID: 19663772]
[5]
Zak K, Pecak A, Rys B, Wladyka B, Dömling A, Weber L, et al. MDM2 and MDMX inhibitors for the treatment of cancer: A patent review (2011-present). Expert Opin Ther Pat 2013; 23(4): 425-48.
[http://dx.doi.org/10.1517/13543776.2013.765405] [PMID: 23374098]
[6]
Deng J, Dayam R, Neamati N. Patented small molecule inhibitors of p53-MDM2 interaction. Expert Opin Ther Pat 2006; 16(2): 165-88.
[http://dx.doi.org/10.1517/13543776.16.2.165] [PMID: 20141510]
[7]
Weber L. Patented inhibitors of p53-MDM2 interaction (2006 - 2008). Expert Opin Ther Pat 2010; 20(2): 179-91.
[http://dx.doi.org/10.1517/13543770903514129] [PMID: 20100001]
[8]
Kamal A, Mohammed AA, Shaik TB. p53-MDM2 inhibitors: Patent review (2009 - 2010). Expert Opin Ther Pat 2012; 22(2): 95-105.
[http://dx.doi.org/10.1517/13543776.2012.656593] [PMID: 22316395]
[9]
Surget S, Khoury MP, Bourdon JC. Uncovering the role of p53 splice variants in human malignancy: A clinical perspective. OncoTargets Ther 2013; 7(7): 57-68.
[PMID: 24379683]
[10]
Lodish HF. Molecular Cell Biology. 4th ed. W.H. Freeman: New York, USA 2000.
[11]
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013; 6(269): pl1.
[http://dx.doi.org/10.1126/scisignal.2004088] [PMID: 23550210]
[12]
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2(5): 401-4.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0095] [PMID: 22588877]
[13]
Moll UM, Petrenko O. The MDM2-p53 interaction. Mol Cancer Res 2003; 1(14): 1001-8.
[PMID: 14707283]
[14]
Momand J, Wu HH, Dasgupta G. MDM2-master regulator of the p53 tumor suppressor protein. Gene 2000; 242(1-2): 15-29.
[http://dx.doi.org/10.1016/S0378-1119(99)00487-4] [PMID: 10721693]
[15]
Chène P. Inhibition of the p53-MDM2 interaction: Targeting a protein-protein interface. Mol Cancer Res 2004; 2(1): 20-8.
[PMID: 14757842]
[16]
Espadinha M, Barcherini V, Lopes EAL, Santos MMM. An update on MDMX and dual MDM2/X inhibitors. Curr Top Med Chem 2018; 18(8): 647-60.
[http://dx.doi.org/10.2174/1568026618666180604080119] [PMID: 29866007]
[17]
Bielskienė K, Bagdonienė L, Mozūraitienė J, Kazbarienė B, Janulionis E. E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma. Medicina (Kaunas) 2015; 51(1): 1-9.
[http://dx.doi.org/10.1016/j.medici.2015.01.007] [PMID: 25744769]
[18]
Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M, et al. MDMX: A novel p53-binding protein with some functional properties of MDM2. EMBO J 1996; 15(19): 5349-57.
[http://dx.doi.org/10.1002/j.1460-2075.1996.tb00919.x] [PMID: 8895579]
[19]
Chang YS, Graves B, Guerlavais V, Tovar C, Packman K, To K-H, et al. Stapled α-helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci USA 2013; 110(36): E3445-54.
[http://dx.doi.org/10.1073/pnas.1303002110] [PMID: 23946421]
[20]
Saiki AY, Caenepeel S, Cosgrove E, Su C, Boedigheimer M, Oliner JD. Identifying the determinants of response to MDM2 inhibition. Oncotarget 2015; 6(10): 7701-12.
[http://dx.doi.org/10.18632/oncotarget.3116] [PMID: 25730903]
[21]
Wilkening S, Bermejo JL, Hemminki K. MDM2 SNP309 and cancer risk: A combined analysis. Carcinogenesis 2007; 28(11): 2262-7.
[http://dx.doi.org/10.1093/carcin/bgm191] [PMID: 17827408]
[22]
Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res 1998; 26(15): 3453-9.
[http://dx.doi.org/10.1093/nar/26.15.3453] [PMID: 9671804]
[23]
Toledo F, Wahl GM. Regulating the p53 pathway: In vitro hypotheses, in vivo veritas. Nat Rev Cancer 2006; 6(12): 909-23.
[http://dx.doi.org/10.1038/nrc2012] [PMID: 17128209]
[24]
Kato S, Ross JS, Gay L, Dayyani F, Roszik J, Subbiah V, et al. Analysis of MDM2 amplification: Next-generation sequencing of patients with diverse malignancies. JCO Precis Oncol 2018; 2018: 1-14.
[http://dx.doi.org/10.1200/PO.17.00235] [PMID: 30148248]
[25]
Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303(5659): 844-8.
[http://dx.doi.org/10.1126/science.1092472] [PMID: 14704432]
[26]
Fedorova O, Daks A, Petrova V, Petukhov A, Lezina L, Shuvalov O, et al. Novel isatin-derived molecules activate p53 via interference with MDM2 to promote apoptosis. Cell Cycle 2018; 17(15): 1917-30.
[http://dx.doi.org/10.1080/15384101.2018.1506664] [PMID: 30109812]
[27]
Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding Y, Gao W, et al. Structure-based design of potent non-peptide MDM2 inhibitors. J Am Chem Soc 2005; 127(29): 10130-1.
[http://dx.doi.org/10.1021/ja051147z] [PMID: 16028899]
[28]
Wang S, Ding K, Lu Y, et al. Small molecule inhibitors of MDM2 and uses thereof WO2006091646. (2006).
[29]
Ding K, Lu Y, Nikolovska-Coleska Z, Wang G, Qiu S, Shangary S, et al. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 2006; 49(12): 3432-5.
[http://dx.doi.org/10.1021/jm051122a] [PMID: 16759082]
[30]
Shangary S, Qin D, McEachern D, Miller R, Nikolovska-Coleska Z, Liu M, et al. A novel orally active MDM2 inhibitor (MI-219) activates the 53.AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics. San Francisco, USA October 2007.
[31]
Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci USA 2008; 105(10): 3933-8.
[http://dx.doi.org/10.1073/pnas.0708917105] [PMID: 18316739]
[32]
Yu S, Qin D, Shangary S, Chen J, Wang G, Ding K, et al. Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 2009; 52(24): 7970-3.
[http://dx.doi.org/10.1021/jm901400z] [PMID: 19928922]
[33]
Sosin AM, Burger AM, Siddiqi A, Abrams J, Mohammad RM, Al-Katib AM. HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J Hematol Oncol 2012; 5(57): 57.
[http://dx.doi.org/10.1186/1756-8722-5-57] [PMID: 22989009]
[34]
Zheng M, Yang J, Xu X, Sebolt JT, Wang S, Sun Y. Efficacy of MDM2 inhibitor MI-219 against lung cancer cells alone or in combination with MDM2 knockdown, a XIAP inhibitor or etoposide. Anticancer Res 2010; 30(9): 3321-31.
[PMID: 20944104]
[35]
Vu B, Wovkulich P, Pizzolato G, Lovey A, Ding Q, Jiang N, et al. Discovery of RG7112: A small-molecule MDM2 inhibitor in clinical development. ACS Med Chem Lett 2013; 4(5): 466-9.
[http://dx.doi.org/10.1021/ml4000657] [PMID: 24900694]
[36]
Bartkovitz DJ, Chu XJ, Ding Q, et al. Spiroindolinone pyrrolidines US20100939234. (2010).
[37]
Zhang Z, Ding Q, Liu JJ, Zhang J, Jiang N, Chu XJ, et al. Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy. Bioorg Med Chem 2014; 22(15): 4001-9.
[http://dx.doi.org/10.1016/j.bmc.2014.05.072] [PMID: 24997575]
[38]
Zhang Z, Chu XJ, Liu JJ, Ding Q, Zhang J, Bartkovitz D, et al. Discovery of potent and orally active p53-MDM2 inhibitors RO5353 and RO2468 for potential clinical development. ACS Med Chem Lett 2013; 5(2): 124-7.
[http://dx.doi.org/10.1021/ml400359z] [PMID: 24900784]
[39]
Mohammad RM, Wu J, Azmi AS, Aboukameel A, Sosin A, Wu S, et al. An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals. Mol Cancer 2009; 8(115): 115.
[http://dx.doi.org/10.1186/1476-4598-8-115] [PMID: 19958544]
[40]
Zhao Y, Yu S, Sun W, Liu L, Lu J, McEachern D, et al. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J Med Chem 2013; 56(13): 5553-61.
[http://dx.doi.org/10.1021/jm4005708] [PMID: 23786219]
[41]
MDM2 p53 binding protein homolog (MDM2; HDM2); p53. SciBX: Science-Business eXchange website. Available at. www.nature.com/scibx/journal/v6/n21/full/scibx.2013.515.html (Accessed on: January 26, 2019)
[42]
Khoury K, Popowicz GM, Holak TA, Dömling A. The p53-MDM2/MDMX axis - A chemotype perspective. MedChemComm 2011; 2(4): 246-60.
[http://dx.doi.org/10.1039/c0md00248h] [PMID: 24466404]
[43]
Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barrière C, et al. SAR405838: An optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res 2014; 74(20): 5855-65.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0799] [PMID: 25145672]
[44]
Aguilar A, Sun W, Liu L, Lu J, McEachern D, Bernard D, et al. Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannich ring-opening-cyclization reaction mechanism in spiro-oxindoles. J Med Chem 2014; 57(24): 10486-98.
[http://dx.doi.org/10.1021/jm501541j] [PMID: 25496041]
[45]
Allen JG, Bourbeau MP, Wohlhieter GE, Bartberger MD, Michelsen K, Hungate R, et al. Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein interaction. J Med Chem 2009; 52(22): 7044-53.
[http://dx.doi.org/10.1021/jm900681h] [PMID: 19856920]
[46]
Bartberger MD, Gonzalez Buenrostro A, Beck H P. Chen, X., Connors, R.V., Deignan, J., Duquette, J., Eksterowicz, J., Fisher, B., Fox, B.M., Fu, J., Fu, Z., Gonzalez Lopez De Turiso, F., Gribble, Jr., M.W., Gustin, D.J., Heath, J.A., Huang, X., Jiao, X., Johnson, M., Kayser, F., Kopecky, D.J., Lai, S., Li, Y. Li, Z., Liu, J., Low, J.D., Lucas, B.S., Ma, Z., McGee, L., McIntosh, J., McMinn, D., Medina, J.C., Mihalic, J.T., Olson, S.H., Rew, Y., Roveto, P.M., Sun, D., Wang, X., Wang, Y., Yan, X., Yu, M., Zhu, J. Piperidinone Derivatives as MDM2 inhibitors for the treatment of cancer WO2011153509. (2011).
[47]
Rew Y, Sun D, Gonzalez-Lopez De Turiso F, Bartberger MD, Beck HP, Canon J, et al. Structure-based design of novel inhibitors of the MDM2-p53 interaction. J Med Chem 2012; 55(11): 4936-54.
[http://dx.doi.org/10.1021/jm300354j] [PMID: 22524527]
[48]
Rew Y, Sun D. Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem 2014; 57(15): 6332-41.
[http://dx.doi.org/10.1021/jm500627s] [PMID: 24967612]
[49]
Gollner A, Rudolph D, Arnhof H, Bauer M, Blake SM, Boehmelt G, et al. Discovery of novel spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds as chemically stable and orally active inhibitors of the mDM2-p53 interaction. J Med Chem 2016; 59(22): 10147-62.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00900] [PMID: 27775892]
[50]
Uoto K, Sugimoto Y, Naito H, Miyazaki M, Yoshida K, Aonuma M. Imidazothiazole derivative having proline ring structure WO2010082612. (2010).
[51]
Sugimoto Y, Uoto K, Miyazaki M, et al. Dispiropyrrolidine derivative WO2012121361. (2012).
[52]
Berghausen J, Buschmann N, Furet P, et al. Substituted isoquinolinones and quinazolinones WO2011076786. (2011).
[53]
Canon J, Osgood T, Olson SH, Saiki AY, Robertson R, Yu D, et al. The MDM2 inhibitor AMG 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents. Mol Cancer Ther 2015; 14(3): 649-58.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0710] [PMID: 25567130]
[54]
Jeay S, Ferretti S, Holzer P, Fuchs J, Chapeau EA, Wartmann M, et al. Dose and schedule determine distinct molecular mechanisms underlying the efficacy of the p53-MDM2 inhibitor HDM201. Cancer Res 2018; 78(21): 6257-67.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-0338] [PMID: 30135191]
[55]
Wu CE, Esfandiari A, Ho YH, Shepherd C, Mahdi AK, Aptullahoglu E, et al. Abstract 2151: Inhibition of WIP1/PPM1D phosphatase by GSK2830371 potentiates the growth inhibitory and cytotoxic activity of MDM2 antagonists (nutlin-3, RG7388 and HDM201) in cutaneous melanoma cells.AACR Annual Meeting 2017. Washington, DC, USA April, 2017.
[56]
Ishizawa J, Nakamaru K, Seki T, Tazaki K, Kojima K, Chachad D, et al. Predictive gene signatures determine tumor sensitivity to MDM2 inhibition. Cancer Res 2018; 78(10): 2721-31.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-0949] [PMID: 29490944]
[57]
Rudolph D, Gollner A, Blake S, Rinnenthal J, Wernitznig A, Weyer-Czernilofsky U, et al. BI 907828: A novel, potent MDM2 inhibitor that is suitable for high-dose intermittent schedules.AACR Annual Meeting 2018. Chicago, USA 2018.
[58]
Chen H, Luo D, Zhang L, Lin X, Luo Q, Yi H, et al. Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells. Oncotarget 2017; 8(26): 43008-22.
[http://dx.doi.org/10.18632/oncotarget.17398] [PMID: 28498808]
[59]
Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem 2013; 56(14): 5979-83.
[http://dx.doi.org/10.1021/jm400487c] [PMID: 23808545]
[60]
Bartkovitz DJ, Chu XJ, Vu BT, Zhao C, Fishlock D. Substituted pyrrolidine-2-carboxamides US8993614. (2015).
[61]
Bartkovitz DJ, Chu XJ, Ehrlich GK, et al. Substituted pyrrolidine-2-carboxamides US9371280. (2016).
[62]
Higgins B, Tovar C, Glen K, Railkar A, Filipovic Z, Qureshi F, et al. Preclinical activity of MDM2 antagonist RO6839921, a pegylated prodrug for intravenous administration.AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics. Boston, MA, USA November 2015.
[63]
Razak A, Gore L, Britten CD, Miller WH, Uy GL, Nichols G, et al. A Phase I study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, for Intravenous (IV) administration in patients with advanced solid tumors.EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Munich, Germany November, 2016.
[http://dx.doi.org/10.1016/S0959-8049(16)32645-4]
[64]
Chen L, Pastorino F, Berry P, Bonner J, Kirk C, Wood KM, et al. Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma. Int J Cancer 2019; 144(12): 3146-59.
[http://dx.doi.org/10.1002/ijc.32058] [PMID: 30536898]
[65]
Yee K, Uy G, Assouline S, Britten CD, Zhi J, Blotner S, et al. A phase I study of the MDM2 antagonist RO6839921, a pegylated intravenous prodrug of idasanutlin, in patients with AML. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, Philadelphia, USA (2017). Eur J Cancer 2016; 69(1): S21-2.
[66]
Higgins B, Kolinsky K, Nichols G, Packman K, Su F. Combination therapy for proliferative disorders US20130245039. (2013).
[67]
Higgins B, Kolinsky K, Nichols G, Packman K, Su F. Combination therapy for proliferative disorders US9216170. (2015).
[68]
Chu X-J, Lovey AJ, Vu BT, Zhao C. Novel imidazolines as dual inhibitors of MDM2 and MDMX WO2014082889. (2014).
[69]
Higgins B, Nichols G, Packman K. Combination of Ro5503781 and capecitabine for cancer therapy WO2014202492. (2014).
[70]
Higgins B, Nichols G, Packman K. Combination of Ro5503781, capecitabine and oxaliplantin for cancer therapy WO2014202497. (2014).
[71]
Higgins B, Nichols G, Packman K. Combination treatment for acute myeloid leukemia (AML) US20150157603. (2015).
[72]
Higgins B, Nichols G, Packman K. Combination treatment for acute myeloid leukemia (AML) US9956243. (2018).
[73]
Klein C, Herting F, Dangl M. Combination therapy of an anti CD20 antibody with a Bcl-2 inhibitor and a MDM2 inhibitor WO2016188935. (2016).
[74]
Blotner SD, Chen G, Jukofsky L, et al. Methods for personalizing patient cancer therapy with an MDM2 antagonist WO2016055497. (2016).
[75]
Wang S, Sun W, Aguilar A, Garcia-Echeverria C. Spirooxindole MDM2 antagonists WO2012155066. (2012).
[76]
Wang S, Aguilar A, Liu L, Lu J, McEachern D. MDM2 inhibitors and therapeutic methods using the same WO2015161032. (2015).
[77]
Bartberger MD, Beck HP, Chen X, et al. Heterocyclic compounds as MDM2 inhibitors for the treatment of cancer WO2013049250. (2013).
[78]
Gonzalez AZ, Eksterowicz J, Bartberger MD, Beck HP, Canon J, Chen A, et al. Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction. J Med Chem 2014; 57(6): 2472-88.
[http://dx.doi.org/10.1021/jm401767k] [PMID: 24548297]
[79]
Bartberger MD, Beck HP, Degraffenreid MR, et al. Cismorpholinone and other compounds as MDM2 inhibitors for the treatment of cancer WO2014130470. (2014).
[80]
Gonzalez Buenrostro A, Li Y, Medina J, Olson S. Heteroaryl acid morpholinone compounds as MDM2 inhibitors for the treatment of cancer WO2014151863. (2014).
[81]
Gonzalez AZ, Li Z, Beck HP, Canon J, Chen A, Chow D, et al. Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres. J Med Chem 2014; 57(7): 2963-88.
[http://dx.doi.org/10.1021/jm401911v] [PMID: 24601644]
[82]
Rew Y. Benzoic acid derivative MDM2 inhibitor for the treatment of cancer US20140243372. (2014).
[83]
Rew Y, Sun D, Yan X, Beck HP, Canon J, Chen A, et al. Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction. J Med Chem 2014; 57(24): 10499-511.
[http://dx.doi.org/10.1021/jm501550p] [PMID: 25384157]
[84]
Bio M, Caille S, Cochran B, Fang Y, Vounatsos F, Wortman S. Processes of making and crystalline forms of A MDM2 inhibitor US20140364455. (2014).
[85]
Bio M, Caille S, Cochran B, Fang Y, Vounatsos F, Wortman S. Processes of making and crystalline forms of a MDM2 inhibitor US9376386. (2016).
[86]
Saiki AY, Caenepeel S, Yu D, Lofgren JA, Osgood T, Robertson R, et al. MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways. Oncotarget 2014; 5(8): 2030-43.
[http://dx.doi.org/10.18632/oncotarget.1918] [PMID: 24810962]
[87]
Caenepeel S, Canon J, Hughes P, Oliner JD, Saiki AY, Rickles RJ. Combination therapy including an MDM2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers US20160287569. (2016).
[88]
Erba HP, Becker PS, Shami PJ, Grunwald MR, Flesher DL, Zhang Y, et al. Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Blood Adv 2019; 3(13): 1939-49.
[http://dx.doi.org/10.1182/bloodadvances.2019030916] [PMID: 31253596]
[89]
Gollner A, Kofink C, Ramharter J, Weinstabl H, Wunberg T. Spiro[3h-indole-3,2’-pyrrolidin]-2(1h)-one derivatives and their use as MDM2-p53 inhibitors WO2015155332. (2015).
[90]
Gollner A, Kofink C, Ramharter J, Weinstabl H, Wunberg T. Spiro[3H-indole-3,2’-pyrrolidin]-2(1H)-one compounds and derivatives as MDM2-P53 inhibitors US10138251. (2018).
[91]
Ramharter J, Broeker J, Gille A, et al. New spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as MDM2-p53 inhibitors WO2016026937. (2016).
[92]
Gollner A, Broeker J, Kerres N, et al. Spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as MDM2-p53 inhibitors WO2017060431. (2017).
[93]
Gollner A, Weinstabl H, Fuchs JE, Rudolph D, Garavel G, Hofbauer KS, et al. Targeted synthesis of complex spiro[3h-indole-3,2′-pyrrolidin]-2(1H)-ones by intramolecular cyclization of azomethine ylides: Highly potent MDM2-p53 Inhibitors. ChemMedChem 2019; 14(1): 88-93.
[PMID: 30458062]
[94]
Rinnenthal J, Rudolph D, Blake S, Gollner A, Wernitznig A, Weyer-Czernilofsky U, et al. BI 907828: A highly potent MDM2 inhibitor with low human dose estimation, designed for high-dose intermittent schedules in the clinic.AACR Annual Meeting 2018. Chicago, USA (2018).
[95]
Rudolph D, Reschke M. Anticancer combination therapy WO2018185135. (2018).
[96]
Miyazaki M, Uoto K, Sugimoto Y, Naito H, Yoshida K, Okayama T, et al. Discovery of DS-5272 as a promising candidate: A potent and orally active p53-MDM2 interaction inhibitor. Bioorg Med Chem 2015; 23(10): 2360-7.
[http://dx.doi.org/10.1016/j.bmc.2015.03.069] [PMID: 25882531]
[97]
Nakamaru K, Seki T, Tazaki K, Tse A. Abstract B5: Preclinical characterization of a novel orally-available MDM2 inhibitor DS- 3032b: Anti-tumor profile and predictive biomarkers for sensitivity.AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics. Boston, USA December, 2015.
[98]
Ishizawa J, Nakamaru K, Seki T, Tazaki K, Kojima K, Chachad D, et al. Discovery of predictive gene signatures for tumor sensitivity to MDM2 inhibition in development of a novel MDM2 inhibitor DS-3032b. Blood 2016; 128(22): 2893-3.
[http://dx.doi.org/10.1182/blood.V128.22.2893.2893]
[99]
Yoshida S, Sugimoto Y. Crystal of Dispiropyrrolidine derivative WO2014038606. (2014).
[100]
Tse NA, Nakamaru K, Tazaki K, Watanabe K, Seki T. Gene signatures associated with sensitivity to MDM2 inhibitors WO2015108175. (2015).
[101]
Tse NA, Nakamaru K, Tazaki K, Watanabe K, Seki T. Algorithms for gene signature-based predictor of sensitivity to MDM2 inhibitors WO2016056673. (2016).
[102]
Seki T. Combination method for treating cancer WO2016133194. (2016).
[103]
Seki T. Treatment method combining mdm2 inhibitor and BTK inhibitor WO2016167236. (2016).
[104]
Seki T. Combination therapy method using MDM2 inhibitor and DNA methyltransferase inhibitor WO2018074387. (2018).
[105]
Furet P, Guagnano V, Holzer P, et al. Pyrazolopyrrolidine compounds WO2013080141. (2013).
[106]
Furet P, Guagnano V, Holzer P, et al. Imidazopyrrolidinone compounds WO2013111105. (2013).
[107]
Cotesta S, Furet P, Guagnano V, et al. Pyrrolopyrrolidinone compounds WO2013175417. (2013).
[108]
Furet P, Guagnano V, Holzer P, et al. Substituted purinone compounds WO2014115077. (2014).
[109]
Furet P, Guagnano V, Holzer P, et al. Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the P53/MDM2 interaction WO2014115080. (2014).
[110]
Emerson E, Halilovic E, Wang H-Q, Zubrowski M. Combination of MDM2 inhibitor and BRAF inhibitor and their use WO2015084804. (2015).
[111]
Ferretti S, Jeay S, Halilovic E, Li F, Wang H. Pharmaceutical combinations WO2015097622. (2015).
[112]
Li F, Wang H, Halilovic E, Liang J. Pharmaceutical combinations WO2015097621. (2015).
[113]
Ferretti S, Jeay S. Intermittent dosing of MDM2 inhibitor WO2015198266. (2015).
[114]
Bhatia R. Pharmaceutical combinations and their use WO2016035023. (2016).
[115]
Guerreiro N, Meille C, Wuerthner J. Gdf-15 as a haematological toxicity biomarker WO2017021908. (2017).
[116]
Halilovic E, Emery C. MDM2 inhibitors for treating uveal melanoma WO2017029588. (2017).
[117]
Halilovic E, Caponigro G, Horn-Spirohn T, Lehar J. MDM2 inhibitors and combinations thereof WO2017037579. (2017).
[118]
Caponigro G, Horn-Spirohn T, Lehar J. Combination therapy using Pi3k inhbitor and MDM2 inhibitor WO2017037586. (2017).
[119]
Chapeau E, Durand E, Gembarska A, Jensen MR, Mandon E. Combinations of MDM2 inhibitors and Bcl-xl inhibitors WO2018092064. (2018).
[120]
Halilovic E, Wang Y. Combination of a Bcl-2 inhibitor and a Mdm2 inhibitor, uses and pharmaceutical compositions thereof WO2018158225. (2018).
[121]
Wang H, Ye J, Han B, et al. Chemical process for preparing imidazopyrrolidinone derivatives and intermediates thereof WO2018096440. (2018).
[122]
Ihry R, Kaykas A, Worringer K. Methods and compositions for enhancing gene editing WO2018083606. (2018).
[123]
Sánchez-Rivera FJ, Jacks T. Applications of the CRISPR-Cas9 system in cancer biology. Nat Rev Cancer 2015; 15(7): 387-95.
[http://dx.doi.org/10.1038/nrc3950] [PMID: 26040603]
[124]
Aryal NK, Wasylishen AR, Lozano G. CRISPR/Cas9 can mediate high-efficiency off-target mutations in mice in vivo. Cell Death Dis 2018; 9(11): 1099.
[http://dx.doi.org/10.1038/s41419-018-1146-0] [PMID: 30368519]
[125]
Ricci CG, Chen JS, Miao Y, Jinek M, Doudna JA, McCammon JA, et al. Molecular mechanism of off-target effects in CRISPR-Cas9 bioRxivorg. 2018.
[126]
Ferretti S, Guerreiro N, Jeay S, Jullion A, Meille C, Wuerthner J. Dose and regimen for HDM2-p53 interaction inhibitors WO2018092020. (2018).
[127]
Ferretti S, Guerreiro N, Jeay S, Jullion A, Meille C, Wuerthner J. Dose and regimen for an HDM2-p53 interaction inhibitor in hematological tumors WO2018178925. (2018).
[128]
Cooke V, Visser M S, Wylie A, Yerramilli-Rao P, Zhu X. Protein kinase C inhibitors for treatment of uveal melanoma WO201905359. (2019).
[129]
Caponigro G, Halilovic E, Monaco KA. Combinations of MDM2 inhibitors with inhibitors of ERK for treating cancers WO2019073435. (2019).
[130]
Inga A, De Magalhães Pinto MM, Ataíde Saraiva LH, et al. Inhibitors of p53- MDM2 interaction WO2013105037. (2013).
[131]
Lemos A, Leão M, Soares J, Palmeira A, Pinto M, Saraiva L, et al. Medicinal chemistry strategies to disrupt the p53-MDM2/MDMX interaction. Med Res Rev 2016; 36(5): 789-844.
[http://dx.doi.org/10.1002/med.21393] [PMID: 27302609]
[132]
Errico JP, Mugrage B, Turchi I, et al. Combination therapy with MDM2 and EFGR inhibitors US8658170. (2014).
[133]
Wannian Z, Zhenyuan M, Chunlin Z, et al. Pyrrolidone pyrazole compound and purposes thereof as drugs CN103819476. (2014).
[134]
Wannian Z, Zhenyuan M, Chunlin Z, et al. Pyrrolidone pyrazole compound and purposes thereof as drugs CN103819476. (2016).
[135]
Feder M, Dubin G, Bulkowska U, et al. 1,5-Dihydropyrrol-2-one derivatives as inhibitors of p53-MDM2/MDM4 protein-protein interaction WO2015004610. (2015).
[136]
Feder M, Kalinowska I, Jaszczewska JA, et al. Compounds comprising 1,1ʹ,2,5ʹ-tetrahydrospiro[indole-3,2ʹ-pyrrole]-2,5ʹ- dione system as inhibitors p53-MDM2 protein-protein interaction wo2015189799. (2015).
[137]
Park HG, Park YH, Lee HJ. α-alkyl-α-carbonyl lactam derivatives and their stereoisomers, and pharmaceutical composition containing the same KR101497962. (2015).
[138]
Arora PS, Lao B, Guarracino D, Bonneau R, Drew K. Oxopiperazine helix mimetics as inhibitors of the p53-MDM2 interaction WO2015160914. (2015).
[139]
Chen Y, Ding Q, Sun Y. Spiropyrrolidines as MDM2 inhibitors US9701685. (2017).
[140]
Su Z, Zhang H, Chen Y, Wang W. Small-molecule inhibitor of MDM/MDM<2>, as well as preparation method and applications CN103923067. (2016).
[141]
Chessari G, Howard S, Buck IM, et al. Isoindolinone inhibitors of the MDM2-p53 interaction having anticancer activity WO2017055859. (2017).
[142]
Howard S, Cons BD, St. Denis JD, Griffiths-Jones CM, Hiscock SD, Holvey RS. Burns, A.R., Cousin, D., Dexter, H.L., Parra, G.F., Watts, J.P., Jewell, R., Stockwell, J.A., Hirst, K.L., Lemasson, I.A., Nash, David, J., Osborne, J.D., Priede, J.C., Richards, N.P., Dumas, A.M., Bishop, B.C., Parry-Jones, D., Scott, J.P., Shaunmugham, M.S., Mullens, P.R., Lathbury, D.C., Dixon, D.J., Gaunt, M.J Isoindolinone inhibitors of the MDM2-p53 interaction and process for making them WO2018178691. (2018).
[143]
Xiao F, Ma J, Xiao F, et al. Spirocyclic indolone polyethylene glycol carbonate compound, composition, preparation method and use thereof WO2018027477. (2018).
[144]
Barakat A, Islam MS, Al Majid AM, et al. Substituted spirooxindoles US9822128. (2017).
[145]
Mazhuga AG, Beloglazkina EK, Ivanenkov YA, Beloglazkina AA, Kukushkin ME, Barashkin AA. Method of obtaining dispiroindolinones RU2682678. (2019).
[146]
Fletcher S, Drennen B, Conlon I, Lanning M. Dual inhibitors of the Bcl-2 and HDM2 families through co-mimicry of the BH3 and p53-alpha-helices WO2019040511. (2019).
[147]
Yin L, Yao Z, Li H. Compound capable of being used as tumor inhibitor, preparation method therefor, and application thereof WO2019128877. (2019).
[148]
Feder M, Mazur M, Kalinowska I, et al. 1,2,3',5'- tetrahydro-2'h-spiro[indole-3,1'-pyrrolo[3,4-c]pyrrole]-2,3'-dione compounds as therapeutic agents activating Tp53 WO2019141549. (2019).
[149]
Rossello A, Nuti E, Orlandini E, et al. Compounds with a benzo[a]carbazole structure and use thereof WO2019049024. (2019).
[150]
Nair H, Santhamma B, Nickisch K. Novel cytotoxic agents that preferentially Target Leukemia Inhibitory Factor (LIF) for the treatment of malignancies and as new contraceptive agents WO2016154203. (2016).
[151]
Crew AP, Crews CM, Dong H, Qian Y, Wang J. MDM2- based modulators of proteolysis and associated methods of use US2017008904. (2017).
[152]
Xia J, Xun H, Wang Y, Zhou Z, Gao Q, Zheng B. Synthetic method for p53-MDM2-binding inhibitor dyhydroxyl quinoline derivative CN105017219. (2017).
[153]
Kim HY, Cho ML, Jhun JY, Byun JK. Composition for inhibiting aging comprising MDM2 inhibitor KR20130139512. (2013).
[154]
Oda K, Makii C. Ovarian clear cell adenocarcinoma therapeutic agent JP2018012666. (2018).
[155]
Nathanson D-A, Mai WX, Jung M-E, et al. Compositions and methods for treating cancer US2018052858. (2018).
[156]
Balko J-M, Johnson DB, de Delgado VS, Sanders M. Methods and systems for predicting response to immunotherapies for treatment of cancer US2019284640. (2019).
[157]
Shetty S, Idell S. Inhibition of pulmonary fibrosis with nutlin-3a and peptides WO2014145389. (2014).
[158]
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370(22): 2071-82.
[http://dx.doi.org/10.1056/NEJMoa1402584] [PMID: 24836310]
[159]
Zhao X, Li Y. Methods for treating cognitive deficits associated with fragile X syndrome US2017079977. (2017).
[160]
Fragile X syndrome Genetics Home Reference website Available at. ghr.nlm.nih.gov/condition/fragile-x-syndrome (Accessed on: January 22, 2019)
[161]
David N. Compounds and therapeutic uses US2017281649. (2017).
[162]
Laberge RM, Campisi J, Davalos A, et al. Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders WO2015116740. (2015).
[163]
Lopez-Dominguez JA, Laberge RM, Campisi J, et al. Compositions and methods for treating senescence-associated diseases and disorders US2018193458. (2018).
[164]
Hopkins J, Tsuruda P, Chapman C, et al. Treatment of ophthalmic conditions such as macular degeneration, glaucoma, and diabetic retinopathy using pharmaceutical agents that eliminate senescent cells WO2019033119. (2019).
[165]
Chinta S-J, Campisi J, Andersen JK, et al. Treatment of Parkinson's disease and other conditions caused or mediated by senescent astrocytes using small molecule senolytic agents US2019269675. (2019).
[166]
Iancu-Rubin C, Mosoyan G, Glenn K, Gordon RE, Nichols GL, Hoffman R. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp Hematol 2014; 42(2): 137-45.e5.
[http://dx.doi.org/10.1016/j.exphem.2013.11.012] [PMID: 24309210]
[167]
Mahfoudhi E, Lordier L, Marty C, Pan J, Roy A, Roy L, et al. P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis. Oncotarget 2016; 7(22): 31980-92.
[http://dx.doi.org/10.18632/oncotarget.7881] [PMID: 26959882]
[168]
Ebrahem R, Ahmed B, Kadhem S, Truong Q. Chronic myeloid leukemia: A Case of extreme thrombocytosis causing syncope and myocardial infarction. Cureus 2016; 8(2)e476
[http://dx.doi.org/10.7759/cureus.476] [PMID: 27004153]
[169]
Wu C-E, Koay TS, Esfandiari A, Ho YH, Lovat P, Lunec J. ATM dependent DUSP6 modulation of p53 involved in synergistic targeting of MAPK and p53 pathways with trametinib and MDM2 inhibitors in cutaneous melanoma. Cancers (Basel) 2018; 11(1): 3.
[http://dx.doi.org/10.3390/cancers11010003] [PMID: 30577494]
[170]
Hata AN, Rowley S, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Ji F, et al. Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers. Oncogene 2017; 36(47): 6581-91.
[http://dx.doi.org/10.1038/onc.2017.258] [PMID: 28783173]
[171]
Berberich A, Kessler T, Thomé CM, Pusch S, Hielscher T, Sahm F, et al. Targeting resistance against the MDM2 inhibitor RG7388 in glioblastoma cells by the MEK inhibitor trametinib. Clin Cancer Res 2019; 25(1): 253-65.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-1580] [PMID: 30274984]
[172]
Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: Analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res 2017; 23(15): 4242-50.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-3133] [PMID: 28351930]
[173]
Singavi AK, Menon S, Kilari D, Alqwasmi A, Ritch PS, Thomas JP, et al. 1140PD: Predictive biomarkers for hyper-progression (HP) in response to immune checkpoint inhibitors (ICI)-analysis of somatic alterations (SAs).ESMO 2017 Congress. Madrid, Spain September, 2017.
[174]
Wang HQ, Liang J, Mulford I, Sharp F, Gaulis S, Chen Y, et al. Abstract 5560: PD-1/PD-L1 blockade enhances MDM2 inhibitor activity in p53 wild-type cancers. AACR Annual Meeting 2018. Chicago, IL, USA April, 2018.
[175]
Goyama S, Hayashi Y, Liu X, Shikata S, Tanaka Y, Fukuyama T, et al. A p53-MDM2 interaction inhibitor, DS-5272, inhibits the development of MLL-fusion leukemia with the assistance of tumor immunity. ASH 2017-59th American Society of Hematology Annual Meeting and Exposition. Atlanta, USA December, 2017.
[176]
Rudolph D, Reschke M, Blake S, Rinnenthal J, Wernitznig A, Weyer-Czernilofsky U, et al. BI 907828: A novel, potent MDM2 inhibitor that induces antitumor immunologic memory and acts synergistically with an anti-PD-1 antibody in syngeneic mouse models of cancer.AACR Annual Meeting 2018. Chicago, IL, USA April, 2018.
[177]
Idasanutlin, Ixazomib Citrate, and Dexamethasone in Treating Patients With Relapsed Multiple Myeloma. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT02633059 (Accessed on: October 7, 2019)
[178]
Martinelli G, Pappayannidis C, Yee K, Vey N, Drummond M, Kelly K, et al. Phase 1b results of idasanutlin + cytarabine (ara-c) in Acute Myeloid Leukemia (AML) patients (Pts).21st Congress of the European Hematology Association. Copenhagen, Denmark. June, 2016.
[179]
A Study of Idasanutlin with Cytarabine versus Cytarabine Plus Placebo in Participants with Relapsed or Refractory Acute Myeloid Leukemia (AML). ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT02545283 (Accessed on: October 7, 2019)
[180]
A Study of RO5503781 as a Single Agent or in Combination with Cytarabine in Participants with Acute Myelogenous Leukemia. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT01773408 (Accessed on: October 7, 2019)
[181]
Yee K, Martinelli G, Vey N, Dickinson MJ, Seiter K, Assouline S, et al. Phase 1/1b Study of RG7388, a Potent MDM2 Antagonist, in Acute Myelogenous Leukemia (AML) Patients (Pts). Blood 2014; 124: 116.
[http://dx.doi.org/10.1182/blood.V124.21.116.116]
[182]
A Study of Idasanutlin in Combination with Obinutuzumab in Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and in Combination with Rituximab in R/R Diffuse Large B-Cell Lymphoma (DLBCL) Participants. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT02624986 (Accessed on: October 7, 2019)
[183]
A Study of Obinutuzumab in Combination with Idasanutlin and Venetoclax in Participants with Relapsed or Refractory (R/R) Follicular Lymphoma (FL) or Rituximab in Combination with Idasanutlin and Venetoclax in Participants With R/R Diffuse Large BCell Lymphoma (DLBCL). ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03135262 (Accessed on: October 7, 2019)
[184]
Herting F, Herter S, Friess T, Muth G, Bacac M, Sulcova J, et al. Antitumour activity of the glycoengineered type II anti-CD20 antibody obinutuzumab (GA101) in combination with the MDM2-selective antagonist idasanutlin (RG7388). Eur J Haematol 2016; 97(5): 461-70.
[http://dx.doi.org/10.1111/ejh.12756] [PMID: 26993060]
[185]
A Study of Venetoclax in Combination with Cobimetinib and Venetoclax in Combination with Idasanutlin in Patients Aged >/= 60 Years with Relapsed or Refractory Acute Myeloid Leukemia Who are not Eligible for Cytotoxic Therapy. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT02670044 (Accessed on: October 7, 2019)
[186]
Seipel K, Marques MAT, Sidler C, Mueller BU, Pabst T. MDM2- and FLT3-inhibitors in the treatment of FLT3-ITD acute myeloid leukemia, specificity and efficacy of NVP-HDM201 and midostaurin. Haematologica 2018; 103(11): 1862-72.
[http://dx.doi.org/10.3324/haematol.2018.191650] [PMID: 29976747]
[187]
Daver N. Safety, efficacy, pharmacokinetic (PK) and biomarker analyses of Bcl2 inhibitor Venetoclax (Ven) plus MDM2 inhibitor idasanutlin (idasa) in patients (pts) with Relapsed or Refractory (R/R) AML: A Phase Ib, non-randomized, open-label study.ASH 2018-60th American Society of Hematology Annual Meeting and Exposition. San Diego, USA (2018).
[188]
Pan R, Kojima K, Zheng Z, Ruvolo VR, Nichols G, Leverson JD, et al. Activation of p53 By novel MDM2 antagonist RG7388 Overcomes AML inherent and acquired resistance to Bcl-2 inhibitor ABT-199 (GDC-0199). Blood 2014; 124(21): 2162-2.
[http://dx.doi.org/10.1182/blood.V124.21.2162.2162]
[189]
Roxburgh P, Currie D, Morrison P, Kelly C, Thomson F, McCormick C, et al. Abstract CT027: Safety, pharmacokinetics (PK) & pharmacodynamics (PD) of idasanutlin (idasa), combined with abiraterone (abi)/prednisolone (pred) or enzalutamide (enza) in castrate resistant prostate cancer (CRPC).AACR Annual Meeting 2018. Chicago, IL, USA April, 2018.
[190]
A Trial of Idasanutlin with Abiraterone or Enzalutamide for Men with Prostate Cancer who haven’t had Docetaxel (MAdCaP). Cancer Research UK. Available at. https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-idasanutlin-with-abiraterone-or-enzalutamide-for-men-with-prostate-cancer-who-havent-had (Accessed on: October 7, 2019)
[191]
Mascarenhas J, Lu M, Kosiorek H, Virtgaym E, Xia L, Sandy L, et al. Oral idasanutlin in patients with polycythemia vera. Blood 2019; 134(6): 525-33.
[http://dx.doi.org/10.1182/blood.2018893545] [PMID: 31167802]
[192]
Atezolizumab and Cobimetinib or Idasanutlin in Participants with Stage IV or Unresectable Recurrent Estrogen Receptor Positive Breast Cancer. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03566485 (Accessed on: October 7, 2019)
[193]
Chen L, Rousseau RF, Middleton SA, Nichols GL, Newell DR, Lunec J, et al. Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget 2015; 6(12): 10207-21.
[http://dx.doi.org/10.18632/oncotarget.3504] [PMID: 25844600]
[194]
Zanjirband M, Edmondson RJ, Lunec J. Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer. Oncotarget 2016; 7(26): 40115-34.
[http://dx.doi.org/10.18632/oncotarget.9499] [PMID: 27223080]
[195]
Zanjirband M, Curtin N, Edmondson RJ, Lunec J. Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer. Oncotarget 2017; 8(41): 69779-96.
[http://dx.doi.org/10.18632/oncotarget.19266] [PMID: 29050241]
[196]
Laroche-Clary A, Chaire V, Algeo M-P, Derieppe M-A, Loarer FL, Italiano A. Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas. J Hematol Oncol 2017; 10(1): 123.
[http://dx.doi.org/10.1186/s13045-017-0482-3] [PMID: 28629371]
[197]
Wu C-E, Esfandiari A, Ho Y-H, Wang N, Mahdi AK, Aptullahoglu E, et al. Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma. Br J Cancer 2018; 118(4): 495-508.
[http://dx.doi.org/10.1038/bjc.2017.433] [PMID: 29235570]
[198]
Laroche A, Chaire V, Algeo M-P, Karanian M, Fourneaux B, Italiano A. MDM2 antagonists synergize with PI3K/mTOR inhibition in well-differentiated/dedifferentiated liposarcomas. Oncotarget 2017; 8(33): 53968-77.
[http://dx.doi.org/10.18632/oncotarget.16345] [PMID: 28903316]
[199]
Scott M, Clarke C, Warren F, Drotar M, Jorgensen H, Hyde R, et al. The combination of the MDM2 antagonist, idasanutlin with nilotinib targets primitive chronic myeloid leukemia (CML) cells in vitro and in vivo. In: 23rd Congress of the European Hematology Association. Stockholm, Sweden June, 2018.
[200]
A Study of RO5045337 in Combination with Doxorubicin in Patients with Soft Tissue Sarcoma. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT01605526 (Accessed on: October 7, 2019)
[201]
Chawla SP, Blay JY, Italiano A, Gutierrez M, Le Cesne A, Gomez-Roca CA, et al. Phase Ib study of RG7112 with doxorubicin (D) in advanced soft tissue sarcoma (ASTS). J Clin Oncol 2013; 31: 10514.
[202]
Urso L, Cavallari I, Silic-Benussi M, Biasini L, Zago G, Calabrese F, et al. Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists. Oncotarget 2017; 8(27): 44232-41.
[http://dx.doi.org/10.18632/oncotarget.17790] [PMID: 28562336]
[203]
Sarisozen C, Tan Y, Liu J, Bilir C, Shen L, Filipczak N, et al. MDM2 antagonist-loaded targeted micelles in combination with doxorubicin: Effective synergism against human glioblastoma via p53 re-activation. J Drug Target 2019; 27(5-6): 624-33.
[http://dx.doi.org/10.1080/1061186X.2019.1570518] [PMID: 30656973]
[204]
Saha MN, Jiang H, Jayakar J, Reece D, Branch DR, Chang H. MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther 2010; 9(11): 936-44.
[http://dx.doi.org/10.4161/cbt.9.11.11882] [PMID: 20418664]
[205]
Lu M, Wang X, Li Y, Tripodi J, Mosoyan G, Mascarenhas J, et al. Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells. Blood 2012; 120(15): 3098-105.
[http://dx.doi.org/10.1182/blood-2012-02-410712] [PMID: 22872685]
[206]
Latif AL, Cole JJ, Monteiro Campos J, Clark W, McGarry L, Brock C, et al. Abstract 647: Dual inhibition of MDM2 and BET cooperate to eradicate acute myeloid leukemia.ASH 2015-57th American Society of Hematology Annual Meeting and Exposition. Orlando, USA (2015).
[207]
Conradt L, Henrich A, Wirth M, Reichert M, Lesina M, Algül H, et al. MDM2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death. Int J Cancer 2013; 132(10): 2248-57.
[http://dx.doi.org/10.1002/ijc.27916] [PMID: 23115126]
[208]
Erba HP, Becker PS, Shami PJ, Grunwald MR, Flesher DL, Zhang Y, et al. Dose escalation results of a Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in patients (Pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML).2017 ASCO Annual Meeting. Chicago, IL, USA May, 2017.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.7027]
[209]
Phase A. A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma.ClinicalTrialsgov Available at https://clinicaltrials.gov/ct2/show/NCT02110355 (Accessed on: October 7, 2019)
[210]
Moschos SJ, Sandhu SK, Lewis KD, Sullivan RJ, Johnson DB, Zhang Y, et al. Phase 1 study of the p53-MDM2 inhibitor AMG 232 combined with trametinib plus dabrafenib or trametinib in patients (Pts) with TP53 wild type (TP53WT) metastatic cutaneous melanoma (MCM).2017 ASCO Annual Meeting. Chicago, USA May, 2017.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.2575]
[211]
MDM2 Inhibitor AMG-232, Carfilzomib, Lenalidomide, and Dexamethasone in Treating Patients with Relapsed or Refractory Multiple Myeloma. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03031730 (Accessed on: October 7, 2019)
[212]
Caenepeel S, Canon J, Hughes P, Oliner JD, Rickles RJ, Saiki AY. Combination therapy including an MDM2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers. WO2015070224. (2015).
[213]
MDM2 Inhibitor AMG-232 and Decitabine in Treating Patients with Relapsed, Refractory, or Newly-Diagnosed Acute Myeloid Leukemia. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03041688 (Accessed on: October 7, 2019)
[214]
Study of Safety and Efficacy of HDM201 in Combination with LEE011 in Patients With Liposarcoma. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT02343172 (Accessed on: October 7, 2019)
[215]
Vilgelm AE, Saleh N, Shattuck-Brandt R, Riemenschneider K, Slesur L, Chen S-C, et al. MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. Sci Transl Med 2019; 11(505)eaav7171
[http://dx.doi.org/10.1126/scitranslmed.aav7171] [PMID: 31413145]
[216]
Next Generation Personalized Neuroblastoma Therapy (NEPENTHE). ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT02780128 (Accessed on: October 7, 2019)
[217]
A Phase I Study of LXS196 in Patients with Metastatic Uveal Melanoma. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT02601378 (Accessed on: October 7, 2019)
[218]
Trametinib + HDM201 in CRC Patients with RAS/RAF Mutant and TP53 Wild-type Advanced/Metastatic Colorectal Cancer Mutant and TP53 Wild-type. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03714958 (Accessed on: October 7, 2019)
[219]
Reuther C, Heinzle V, Nölting S, Herterich S, Hahner S, Halilovic E, et al. The HDM2 (MDM2) inhibitor NVP-CGM097 inhibits tumor cell proliferation and shows additive effects with 5-fluorouracil on the p53-p21-Rb-E2F1 cascade in the p53 wild type neuroendocrine tumor cell line GOT1. Neuroendocrinology 2018; 106(1): 1-19.
[http://dx.doi.org/10.1159/000453369] [PMID: 27871087]
[220]
Horn T, Ferretti S, Ebel N, Tam A, Ho S, Harbinski F, et al. High-order drug combinations are required to effectively kill colorectal cancer cells. Cancer Res 2016; 76(23): 6950-63.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-3425] [PMID: 27659046]
[221]
Carita G, Frisch-Dit-Leitz E, Dahmani A, Raymondie C, Cassoux N, Piperno-Neumann S, et al. Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma. Oncotarget 2016; 7(23): 33542-56.
[http://dx.doi.org/10.18632/oncotarget.9552] [PMID: 27507190]
[222]
Wang HQ, Halilovic E, Li X, Liang J, Cao Y, Rakiec DP, et al. Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human ALK mutant neuroblastoma cell lines and xenograft models. eLife 2017. 6e17137
[http://dx.doi.org/10.7554/eLife.17137] [PMID: 28425916]
[223]
Weger VD, Varga A, Jonge MD, Langenberg M, Mergui-Roelvink M, Massard C, et al. A Phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumors. Eur J Cancer 2015; 51(3): S55.
[http://dx.doi.org/10.1016/S0959-8049(16)30169-1]
[224]
Nör F, Warner KA, Zhang Z, Acasigua GA, Pearson AT, Kerk SA, et al. Therapeutic inhibition of the MDM2-p53 interaction prevents recurrence of adenoid cystic carcinomas. Clin Cancer Res 2017; 23(4): 1036-48.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1235] [PMID: 27550999]
[225]
Hoffman-Luca CG, Ziazadeh D, McEachern D, Zhao Y, Sun W, Debussche L, et al. Elucidation of acquired resistance to Bcl-2 and MDM2 inhibitors in acute leukemia in vitro and in vivo. Clin Cancer Res 2015; 21(11): 2558-68.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2506] [PMID: 25754349]
[226]
Milademetan Tosylate and Low-Dose Cytarabine in Treating Participants with Recurrent or Refractory Acute Myeloid Leukemia. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03634228 (Accessed on: October 7, 2019)
[227]
Safety, Tolerability and Pharmacokinetics of Milademetan Alone and with 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS). Clinical- Trials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT02319369 (Accessed on: October 7, 2019)
[228]
Noguchi S, Seki T, Adachi N, Sumi H, Nakano R, Inaki K, et al. Azacitidine (aza) enhances antileukemic activity of the MDM2 inhibitor milademetan in tp53 wild-type acute myeloid leukemia (AML). HemaSphere 2019; 3: 65.
[http://dx.doi.org/10.1097/01.HS9.0000559116.40081.dc]
[229]
DiNardo CD, Rosenthal J, Andreeff M, Zernovak O, Kumar P, Gajee R, et al. Phase 1 dose escalation study of MDM2 inhibitor DS-3032b in patients with hematological malignancies-preliminary results. Blood 2016; 128(22): 593-3.
[230]
Milademetan Plus Quizartinib Combination Study in FLT3-ITD Mutant Acute Myeloid Leukemia (AML). ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03552029 (Accessed on: October 7, 2019)
[231]
Andreeff M, Zhang W, Kumar P, Zernovak O, Daver NG, Isoyama T. Synergistic anti-leukemic activity with combination of FLT3 inhibitor uizartinib and MDM2 inhibitor milademetan in FLT3-ITD mutant/p53 wild-type acute myeloid leukemia models.ASH 2018- 60th American Society of Hematology Annual Meeting and Exposition. San Diego, USA 2018.
[232]
A Phase I/II Trial of APG-115 in Patients with Salivary Gland Carcinoma. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03781986 (Accessed on: October 7, 2019)
[233]
A Study of APG-115 in Combination with Pembrolizumab in Patients with Metastatic Melanomas or Advanced Solid Tumors. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03611868 (Accessed on: October 7, 2019)
[234]
Tolcher AW, Fang DD, Li Y, Tang Y, Ji J, Wang H, et al. 2OA Phase Ib/II study of APG-115 in combination with pembrolizumab in patients with unresectable or metastatic melanomas or advanced solid tumors. Ann Oncol 2019; 30(1)mdz027
[http://dx.doi.org/10.1093/annonc/mdz027] [PMID: 30810171]
[235]
Fang DD, Zhai G, Xu C, Gu Q, Wang J, Zhu S, et al. Abstract 1253: MDM2 inhibitor APG-115 synergizes with CDK4/6 inhibitors in a patient-derived xenograft model of dedifferentiated liposarcoma.AACR Annual Meeting 2019. Atlanta, GA, USA March-April, 2019.
[236]
A Study in Patients with Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 in Combination With BI 754091 and 754111. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03964233 (Accessed on: October 7, 2019)
[237]
Rudolph D, Weyer-Czernilofsky U, Reschke M, Sykora M, Rinnenthal J, Blake S, et al. Abstract 3197: BI-907828, a novel and potent MDM2-p53 antagonist, acts synergistically in a triple combination with anti-PD-1 and anti-LAG-3 antibodies in syngeneic mouse models of cancer.AACR Annual Meeting 2019. Atlanta, GA, USA April, 2019.
[238]
Ravandi F, Gojo I, Patnaik MM, Minden MD, Kantarjian H, Johnson-Levonas AO, et al. A Phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Leuk Res 2016; 48: 92-100.
[http://dx.doi.org/10.1016/j.leukres.2016.07.004] [PMID: 27544076]
[239]
Sallman D, Borate U, Cull EH, Donnellan WB, Komrokji RS, Steidl UG, et al. Phase 1/1b study of the stapled peptide ALRN- 6924, a dual inhibitor of MDMX and MDM2, as monotherapy or in combination with cytarabine for the treatment of relapsed/ refractory AML and advanced MDS with TP53 wild-type.ASH 2017-59th American Society of Hematology Annual Meeting and Exposition. San Diego, USA November, 2018.
[http://dx.doi.org/10.1182/blood-2018-99-118780]
[240]
Phase 1 Study of the Dual MDM2/MDMX Inhibitor ALRN-6924 in Pediatric Cancer. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03654716 (Accessed on: October 7, 2019)
[241]
Safety Study of ALRN-6924 in Patients with Acute Myeloid Leukemia or Advanced Myelodysplastic Syndrome. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT02909972 (Accessed on: October 7, 2019)
[242]
ALRN-6924 and Paclitaxel in Treating Patients with Advanced, Metastatic, or Unresectable Solid Tumors. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT03725436 (Accessed on: October 7, 2019)
[243]
A Study of ALRN-6924 for the Prevention of Topotecan-induced Myelosuppression during Treatment for Small Cell Lung Cancer. ClinicalTrials.gov. Available at. https://clinicaltrials.gov/ct2/show/NCT04022876 (Accessed on: October 7, 2019)
[244]
Cinatl J, Speidel D, Hardcastle I, Michaelis M. Resistance acquisition to MDM2 inhibitors. Biochem Soc Trans 2014; 42(4): 752-7.
[http://dx.doi.org/10.1042/BST20140035] [PMID: 25109953]
[245]
Hoffman-Luca CG, Yang CY, Lu J, Ziazadeh D, McEachern D, Debussche L, et al. Significant differences in the development of acquired resistance to the MDM2 inhibitor SAR405838 between in vitro and in vivo drug treatment. PLoS One 2015; 10(6)e0128807
[http://dx.doi.org/10.1371/journal.pone.0128807] [PMID: 26070072]
[246]
Sallman D. Targeting TP53 mutations in myelodysplastic syndromes. The Hematologist: ASH News & Reports 2018; 15(6)
[247]
Wiegering A, Matthes N, Mühling B, Koospal M, Quenzer A, Peter S, et al. Reactivating p53 and Inducing Tumor Apoptosis (RITA) enhances the response of RITA-sensitive colorectal cancer cells to chemotherapeutic agents 5-fluorouracil and oxaliplatin. Neoplasia 2017; 19(4): 301-9.
[http://dx.doi.org/10.1016/j.neo.2017.01.007] [PMID: 28284059]
[248]
Blandino G, Di Agostino S. New therapeutic strategies to treat human cancers expressing mutant p53 proteins. J Exp Clin Cancer Res 2018; 37(1): 30.
[http://dx.doi.org/10.1186/s13046-018-0705-7] [PMID: 29448954]
[249]
Izetti P, Hautefeuille A, Abujamra AL, de Farias CB, Giacomazzi J, Alemar B, et al. PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines. Invest New Drugs 2014; 32(5): 783-94.
[http://dx.doi.org/10.1007/s10637-014-0090-9] [PMID: 24838627]
[250]
Rao B, Lain S, Thompson AM. p53-Based cyclotherapy: Exploiting the ‘guardian of the genome’ to protect normal cells from cytotoxic therapy. Br J Cancer 2013; 109(12): 2954-8.
[http://dx.doi.org/10.1038/bjc.2013.702] [PMID: 24231949]
[251]
Wiley CD, Schaum N, Alimirah F, Lopez-Dominguez JA, Orjalo AV, Scott G, et al. Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype. Sci Rep 2018; 8(1): 2410.
[http://dx.doi.org/10.1038/s41598-018-20000-4] [PMID: 29402901]
[252]
Carvajal D, Tovar C, Yang H, Vu BT, Heimbrook DC, Vassilev LT. Activation of p53 by MDM2 antagonists can protect proliferating cells from mitotic inhibitors. Cancer Res 2005; 65(5): 1918-24.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3576] [PMID: 15753391]
[253]
Li Y, Saini P, Sriraman A, Dobbelstein M. MDM2 inhibition confers protection of p53-proficient cells from the cytotoxic effects of Wee1 inhibitors. Oncotarget 2015; 6(32): 32339-52.
[http://dx.doi.org/10.18632/oncotarget.5891] [PMID: 26431163]
[254]
Sur S, Pagliarini R, Bunz F, Rago C, Diaz LA, Kinzler KW, et al. A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc Natl Acad Sci USA 2009; 106(10): 3964-9.
[http://dx.doi.org/10.1073/pnas.0813333106] [PMID: 19225112]
[255]
Li Q, Lozano G. Molecular pathways: Targeting MDM2 and MDM4 in cancer therapy. Clin Cancer Res 2013; 19(1): 34-41.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-0053] [PMID: 23262034]
[256]
Hu B, Gilkes DM, Farooqi B, Sebti SM, Chen J. MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J Biol Chem 2006; 281(44): 33030-5.
[http://dx.doi.org/10.1074/jbc.C600147200] [PMID: 16905541]
[257]
Chapeau EA, Gembarska A, Durand EY, Mandon E, Estadieu C, Romanet V, et al. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an ARF-/- mouse model. Proc Natl Acad Sci USA 2017; 114(12): 3151-6.
[http://dx.doi.org/10.1073/pnas.1620262114] [PMID: 28265066]
[258]
Graves B, Thompson T, Xia M, Janson C, Lukacs C, Deo D, et al. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci USA 2012; 109(29): 11788-93.
[http://dx.doi.org/10.1073/pnas.1203789109] [PMID: 22745160]
[259]
Carvajal LA, Neriah DB, Senecal A, Benard L, Thiruthuvanathan V, Yatsenko T, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med 2018; 10(436)eaao3003
[http://dx.doi.org/10.1126/scitranslmed.aao3003] [PMID: 29643228]
[260]
Meric-Bernstam F, Saleh MN, Infante JR, Goel S, Falchook GS, Shapiro G, et al. Phase I trial of a novel stapled peptide ALRN- 6924 disrupting MDMX- and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas.2017 ASCO Annual Meeting. Chicago, IL, USA (2017).
[261]
Teveroni E, Lucà R, Pellegrino M, Ciolli G, Pontecorvi A, Moretti F. Peptides and peptidomimetics in the p53/MDM2/MDM4 circuitry - a patent review. Expert Opin Ther Pat 2016; 26(12): 1417-29.
[http://dx.doi.org/10.1080/13543776.2017.1233179] [PMID: 27603098]
[262]
Lai AC, Crews CM. Induced protein degradation: An emerging drug discovery paradigm. Nat Rev Drug Discov 2017; 16(2): 101-14.
[http://dx.doi.org/10.1038/nrd.2016.211] [PMID: 27885283]
[263]
Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J Med Chem 2019; 62(2): 448-66.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00909] [PMID: 30525597]
[264]
Freeman JA, Espinosa JM. The impact of post-transcriptional regulation in the p53 network. Brief Funct Genomics 2013; 12(1): 46-57.
[http://dx.doi.org/10.1093/bfgp/els058] [PMID: 23242178]
[265]
Mascarenhas J, Lu M, Virtgaym E, Kosiorek H, Stal M, Sandy L, et al. Open Label Phase I Study of Single Agent Oral RG7388 (idasanutlin) in Patients with Polycythemia Vera and Essential Thrombocythemia.ASH 2017-59th American Society of Hematology Annual Meeting and Exposition. Atlanta, USA (2017).
[266]
Brennan RC, Federico S, Bradley C, et al. Targeting the p53 pathway in retinoblastoma with subconjunctival Nutlin-3a. Cancer Res 2011; 71(12): 4205-13.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-0058] [PMID: 21515735]
[267]
Lei H, Rheaume MA, Cui J, Mukai S, Maberley D, Samad A, et al. A novel function of p53: A gatekeeper of retinal detachment. Am J Pathol 2012; 181(3): 866-74.
[http://dx.doi.org/10.1016/j.ajpath.2012.05.036] [PMID: 22901751]
[268]
Chavala SH, Kim Y, Tudisco L, Cicatiello V, Milde T, Kerur N, et al. Retinal angiogenesis suppression through small molecule activation of p53. J Clin Invest 2013; 123(10): 4170-81.
[http://dx.doi.org/10.1172/JCI67315] [PMID: 24018558]
[269]
Childs BG, Gluscevic M, Baker DJ, Laberge R-M, Marquess D, Dananberg J, et al. Senescent cells: An emerging target for diseases of ageing. Nat Rev Drug Discov 2017; 16(10): 718-35.
[http://dx.doi.org/10.1038/nrd.2017.116] [PMID: 28729727]
[270]
Pápai Z, Chen LC, Da Costa D, Blotner S, Vazvaei F, Gleave M, et al. A single-center, open-label study investigating the excretion balance, pharmacokinetics, metabolism, and absolute bioavailability of a single oral dose of [14C]-labeled idasanutlin and an intravenous tracer dose of [13C]-labeled idasanutlin in a single cohort of patients with solid tumors. Cancer Chemother Pharmacol 2019; 84(1): 93-103.
[http://dx.doi.org/10.1007/s00280-019-03851-0] [PMID: 31062077]
[271]
Siu LL, Italiano A, Miller WH, Blay JY, Gietema JA, Bang YJ, et al. Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent second-generation MDM2 antagonist, in patients (pts) with solid tumors.2014 ASCO Annual Meeting. Chicago, USA (2014).
[http://dx.doi.org/10.1200/jco.2014.32.15_suppl.2535]
[272]
Nemunaitis J, Young A, Ejadi S, Miller W, Chen LC, Nichols G, et al. Effects of posaconazole (a strong CYP3A4 inhibitor), two new tablet formulations, and food on the pharmacokinetics of idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors. Cancer Chemother Pharmacol 2018; 81(3): 529-37.
[http://dx.doi.org/10.1007/s00280-018-3521-z] [PMID: 29368050]
[273]
Andreeff M, Kelly KR, Yee K, Assouline S, Strair R, Popplewell L, et al. Results of the Phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res 2016; 22(4): 868-76.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0481] [PMID: 26459177]
[274]
Ray-Coquard I, Blay J-Y, Italiano A, Le Cesne A, Penel N, Zhi J, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: An exploratory proof-of-mechanism study. Lancet Oncol 2012; 13(11): 1133-40.
[http://dx.doi.org/10.1016/S1470-2045(12)70474-6] [PMID: 23084521]
[275]
Gluck WL, Gounder MM, Frank R, Eskens F, Blay JY, Cassier PA, et al. Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma. Invest New Drugs 2019; 1-13.
[http://dx.doi.org/10.1007/s10637-019-00840-1] [PMID: 31359240]
[276]
Welliver M, Van Tine BA, Houghton P, Rudek MA, Pollock RE, Kane JM, et al. MDM2 inhibitor AMG-232 and radiation therapy in treating patients with soft tissue sarcoma with wild-type TP53: A phase IB study (NRG-DT001). J Clin Oncol 2019; 37TPS11076
[277]
Hyman D, Chatterjee M, Langenberg MHG, Lin CC, Suárez C, Tai D, et al. Dose- and regimen-finding Phase I study of NVP-HDM201 in patients (pts) with TP53 wild-type (wt) advanced tumors.EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Munich, Germany (2016).
[http://dx.doi.org/10.1016/S0959-8049(16)32982-3]
[278]
Bauer S, Demetri G, Jeay S, Dummer R, Guerreiro N, Tan DS, et al. A phase I, open-label, multi-center, dose escalation study of oral NVP-CGM097, a p53/HDM2-protein-protein interaction inhibitor, in adult patients with selected advanced solid tumors.ESMO 2016 Congress. Copenhagen, Denmark (2016).
[279]
de Weger VA, de Jonge M, Langenberg MHG, et al. A Phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours. Br J Cancer 2019; 120(3): 286-93.
[http://dx.doi.org/10.1038/s41416-018-0355-8] [PMID: 30585255]
[280]
Gounder MM, Bauer TM, Schwartz GK, Masters T, Carvajal RD, Song S, et al. A Phase 1 study of the MDM2 inhibitor DS-3032b in patients (pts) with advanced solid tumors and lymphomas.2016 ASCO Annual Meeting. Chicago, USA (2016).
[http://dx.doi.org/10.1200/JCO.2016.34.15_suppl.2581]
[281]
Daver NG, Zhang W, Graydon R, Dawra V, Xie J, Kumar P, et al. A Phase I study of milademetan in combination with quizartinib in patients (pts) with newly diagnosed (ND) or relapsed/refractory (R/R) FLT3-ITD acute myeloid leukemia (AML). J Clin Oncol 2019; 37: TPS7067-7.
[282]
Rasco DW, Lakhani NJ, Li Y, Men L, Wang H, Ji J, et al. A Phase I study of a novel MDM2 antagonist APG-115 in patients with advanced solid tumors. J Clin Oncol 2019; 37: 3126.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.3126]
[283]
Zhang X, Wen X, Yang C, Zeng S, Men L, Wang H, et al. A Phase I study of a novel MDM2-P53 antagonist APG-115 in Chinese patients with advanced soft tissue sarcomas. J Clin Oncol 2019; 37: 3124.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.3124]
[284]
Chong CR, Bauer TM, Laurie SA, Patel MR, Yamamoto N, Davenport T, et al. A Phase Ia/Ib, open label, multicenter, dose-escalation study of BI 907828 (MDM2-p53 antagonist) in adult patients with advanced or metastatic solid tumors. J Clin Oncol 2019; 37: TPS3166-6.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.TPS3166]
[285]
Hanna GJ, DeCaprio JA, Mei JHM, McGreivy JS. An open label, multicenter, Phase II study of KRT-232, an oral small molecule inhibitor of MDM2, for the treatment of patients with Merkel Cell Carcinoma (MCC) who have failed treatment with anti-PD-1/L1 immunotherapy. J Clin Oncol 2019; 37: TPS9602-2.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.TPS9602]
[286]
Wagner AJ, Banerji U, Mahipal A, Somaiah N, Hirsch H, Fancourt C, et al. Phase I trial of the human double minute 2 inhibitor MK-8242 in patients with advanced solid tumors. J Clin Oncol 2017; 35(12): 1304-11.
[http://dx.doi.org/10.1200/JCO.2016.70.7117] [PMID: 28240971]
[287]
Tabernero J, Dirix L, Schoffski P, Cervantes A, Lopez-Martin JA, Capdevila J, et al. A Phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors. Clin Cancer Res 2011; 17(19): 6313-21.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1101] [PMID: 21831953]

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