Login Register Cart 0
Generic placeholder image

Technology Transfer and Entrepreneurship (Discontinued)

Editor-in-Chief

ISSN (Print): 2213-8099
ISSN (Online): 2213-8102

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Targeted Protein Degradation: "The Gold Rush is On!"

Author(s): Daria Kotlarek, Agata Pawlik, Maria Sagan, Marta Sowała, Alina Zawiślak-Architek and Michał J. Walczak*

Volume 7, Issue 1, 2020

Page: [4 - 16] Pages: 13

DOI: 10.2174/2213809907666200130111436

Price: $65

Abstract

Targeted Protein Degradation (TPD) is an emerging new modality of drug discovery that offers unprecedented therapeutic benefits over traditional protein inhibition. Most importantly, TPD unlocks the untapped pool of the proteome that to date has been considered undruggable. Captor Therapeutics (Captor) is the fourth global, and first European, company that develops small molecule drug candidates based on the principles of targeted protein degradation. Captor is located in Basel, Switzerland and Wroclaw, Poland and exploits the best opportunities of the two sites – experience and non-dilutive European grants, and talent pool, respectively. Through over $38 M of funding, Captor has been active in three areas of TPD: molecular glues, bi-specific degraders and direct degraders, ObteronsTM.

Keywords: Targeted protein degradation, PROTAC, degraders, proteasome, cancer, oncology.

« Previous Next »
[1]
Deshaies RJ. Protein degradation: Prime time for PROTACs. Nat Chem Biol 2015; 11(9): 634-5.
[http://dx.doi.org/10.1038/nchembio.1887] [PMID: 26284668]
[2]
Tanaka K. The proteasome: overview of structure and functions. Proc Jpn Acad, Ser B, Phys Biol Sci 2009; 85(1): 12-36.
[http://dx.doi.org/10.2183/pjab.85.12]
[3]
Tan X, Calderon-Villalobos LIA, Sharon M, et al. Mechanism of auxin perception by the TIR1 ubiquitin ligase. Nature 2007; 446(7136): 640-5.
[http://dx.doi.org/10.1038/nature05731] [PMID: 17410169]
[4]
Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA 2001; 98(15): 8554-9.
[http://dx.doi.org/10.1073/pnas.141230798] [PMID: 11438690]
[5]
Scudellari M. Protein-slaying drugs could be the next blockbuster therapies. Nature 2019; 567(7748): 298-300.
[http://dx.doi.org/10.1038/d41586-019-00879-3] [PMID: 30894734]
[6]
Kenten JH, Roberts SF. Inventor; PROTEINIX Inc, assignee Controlling protein levels in eucaryotic organisms United States patent US6306663(B1). 2001.
[7]
Schneekloth AR, Pucheault M, Tae HS, Crews CM. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg Med Chem Lett 2008; 18(22): 5904-8.
[http://dx.doi.org/10.1016/j.bmcl.2008.07.114] [PMID: 18752944]
[8]
Toure M, Crews CM. Small-molecule PROTACS: New approaches to protein degradation. Wiley-VCH Verlag 2016; 55: 1966-73.
[9]
Salami J, Crews CM. Waste disposal-An attractive strategy for cancer therapy. Science 2017; 355(6330): 1163-7.
[10]
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]
[11]
Kargbo RB. PROTAC degradation of IRAK4 for the treatment of neurodegenerative and cardiovascular diseases. ACS Med Chem Lett 2019; 10(9): 1251-2.
[http://dx.doi.org/10.1021/acsmedchemlett.9b00385] [PMID: 31531192]
[12]
Lu M, Liu T, Jiao Q, et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur J Med Chem 2018; 146: 251-9.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.063] [PMID: 29407955]
[13]
Bondeson DP, Mares A, Smith IED, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol 2015; 11(8): 611-7.
[http://dx.doi.org/10.1038/nchembio.1858] [PMID: 26075522]
[14]
Neklesa TK, Winkler JD, Crews CM. Targeted protein degradation by PROTACs. Pharmacol Ther 2017; 174: 138-44.
[http://dx.doi.org/10.1016/j.pharmthera.2017.02.027] [PMID: 28223226]
[15]
Lai A, Kahraman M, Govek S, et al. Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J Med Chem 2015; 58(12): 4888-904.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00054] [PMID: 25879485]
[16]
Raina K, Lu J, Qian Y, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci USA 2016; 113(26): 7124-9.
[http://dx.doi.org/10.1073/pnas.1521738113] [PMID: 27274052]
[17]
Cyrus K, Wehenkel M, Choi EY, Lee H, Swanson H, Kim KB. Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs. ChemMedChem 2010; 5(7): 979-85.
[http://dx.doi.org/10.1002/cmdc.201000146] [PMID: 20512796]
[18]
Salami J, Alabi S, Willard RR, et al. Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun Biol 2018; 1(1): 100.
[http://dx.doi.org/10.1038/s42003-018-0105-8] [PMID: 30271980]
[19]
Brand M, Jiang B, Bauer S, et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem Biol 2019; 26(2): e300-6.
[http://dx.doi.org/10.1016/j.chembiol.2018.11.006] [PMID: 30595531]
[20]
Huang HT, Dobrovolsky D, Paulk J, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol 2018; 25(1): 88-99.
[http://dx.doi.org/10.1016/j.chembiol.2017.10.005] [PMID: 29129717]
[21]
Bondeson DP, Smith BE, Burslem GM, et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem Biol 2018; 25(1): 78-87.
[http://dx.doi.org/10.1016/j.chembiol.2017.09.010] [PMID: 29129718]
[22]
Mullard A. First targeted protein degrader hits the clinic. Nat Rev Drug Discov 2019; 18: 237-9.
[http://dx.doi.org/10.1038/d41573-019-00043-6] [PMID: 30936511]
[23]
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46(1-3): 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[24]
Churcher I. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones. J Med Chem 2018; 61(2): 444-52.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01272] [PMID: 29144739]
[25]
Hayashi K, Tan X, Zheng N, et al. Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling. Proc Natl Acad Sci USA 2008; 105(14): 5632-7.
[http://dx.doi.org/10.1073/pnas.0711146105] [PMID: 18391211]
[26]
Fischer ES, Park E, Eck MJ, Thomä NH. SPLINTS: small-molecule protein ligand interface stabilizers. Curr Opin in Struct Biol 2016; 37: 115-22.
[http://dx.doi.org/10.1016/j.sbi.2016.01.004] [PMID: 26829757]
[27]
Che Y, Gilbert AM, Shanmugasundaram V, Noe MC. Inducing protein-protein interactions with molecular glues. Bioorg Med Chem Lett 2018; 28(15): 2585-92.
[http://dx.doi.org/10.1016/j.bmcl.2018.04.046] [PMID: 29980357]
[28]
Hughes SJ, Ciulli A. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Essays in Biochem 2017; 61(5): 505-16.
[http://dx.doi.org/10.1042/EBC20170041]
[29]
Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004; 4(4): 314-22.
[http://dx.doi.org/10.1038/nrc1323] [PMID: 15057291]
[30]
Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341(21): 1565-71.
[http://dx.doi.org/10.1056/NEJM199911183412102] [PMID: 10564685]
[31]
Krönke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014; 343(6168): 301-5.
[http://dx.doi.org/10.1126/science.1244851] [PMID: 24292625]
[32]
Krönke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 2015; 523(7559): 183-8.
[http://dx.doi.org/10.1038/nature14610] [PMID: 26131937]
[33]
Matyskiela ME, Zhang W, Man HW, et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J Med Chem 2018; 61(2): 535-42.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01921] [PMID: 28425720]
[34]
Hagner PR, Man HW, Fontanillo C, et al. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood 2015; 126(6): 779-89.
[http://dx.doi.org/10.1182/blood-2015-02-628669] [PMID: 26002965]
[35]
Matyskiela ME, Lu G, Ito T, et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature 2016; 535(7611): 252-7.
[http://dx.doi.org/10.1038/nature18611] [PMID: 27338790]
[36]
Hansen JD, Condroski K, Correa M, et al. Protein degradation via CRL4CRBN ubiquitin ligase: discovery and structure-activity relationships of novel glutarimide analogs that promote degradation of aiolos and/or GSPT1. J Med Chem 2018; 61(2): 492-503.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01911] [PMID: 28358507]
[37]
Han T, Goralski M, Gaskill N, et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 2017; 356(6363): 3755.
[http://dx.doi.org/10.1126/science.aal3755]
[38]
Uehara T, Minoshima Y, Sagane K, et al. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat Chem Biol 2017; 13(6): 675-80.
[http://dx.doi.org/10.1038/nchembio.2363] [PMID: 28437394]
[39]
An open-label, randomized, phase ii study of the efficacy and safety of Indisulam (E7070) in combination with Capecitabine. ClinicalTrailsgov 2017. Available from:. https://clinicaltrials.gov/ct2/ show/NCT00165880
[40]
Gu S, Cui D, Chen X, Xiong X, Zhao Y. PROTACs: An emerging targeting technique for protein degradation in drug discovery. BioEssays 2018; 40(4) e1700247
[41]
Pei H, Peng Y, Zhao Q, Chen Y. Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery. RSC Advances 2019; 9(30): 16967-76.
[http://dx.doi.org/10.1039/C9RA03423D]
[42]
Itoh Y, Ishikawa M, Naito M, Hashimoto Y. Protein knockdown using methyl bestatin-ligand hybrid molecules: design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins. J Am Chem Soc 2010; 132(16): 5820-6.
[http://dx.doi.org/10.1021/ja100691p] [PMID: 20369832]
[43]
Fischer ES, Böhm K, Lydeard JR, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 2014; 512(7512): 49-53.
[http://dx.doi.org/10.1038/nature13527] [PMID: 25043012]
[44]
Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science 2010; 327(5971): 1345-50.
[http://dx.doi.org/10.1126/science.1177319]
[45]
Lu J, Qian Y, Altieri M, et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem Biol 2015; 22(6): 755-63.
[http://dx.doi.org/10.1016/j.chembiol.2015.05.009] [PMID: 26051217]
[46]
Winter GE, Buckley DL, Paulk J, et al. Selective target protein degradation via phthalimide conjugation. Science 2015; 348(6241): 1376-81.
[47]
Chopra R, Sadok A, Collins I. A critical evaluation of the approaches to targeted protein degradation for drug discovery. Drug Discov Today Technol 2019; 31: 5-13.
[http://dx.doi.org/10.1016/j.ddtec.2019.02.002]
[48]
Neklesa TK, Tae HS, Schneekloth AR, et al. Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nat Chem Biol 2011; 7(8): 538-43.
[http://dx.doi.org/10.1038/nchembio.597] [PMID: 21725302]
[49]
Tellez A. The Case for targeted protein degradation | LinkedIn 2019. Available from:. https://www. linkedin.com/pulse/case-targeted-protein-degradation-andres-tellez/
[50]
Oo ML, Thangada S, Wu MT, et al. Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem 2007; 282(12): 9082-9.
[http://dx.doi.org/10.1074/jbc.M610318200] [PMID: 17237497]
[51]
Oo ML, Chang S-H, Thangada S, et al. Engagement of S1P1-degradative mechanisms leads to vascular leak in mice. J Clin Invest 2011; 121(6): 2290-300.
[http://dx.doi.org/10.1172/JCI45403] [PMID: 21555855]
[52]
Valentine WJ, Godwin VI, Osborne DA, et al. FTY720 (Gilenya) phosphate selectivity of sphingosine 1-phosphate receptor subtype 1 (S1P1) G protein-coupled receptor requires motifs in intracellular loop 1 and transmembrane domain 2. J Biol Chem 2011; 286(35): 30513-25.
[http://dx.doi.org/10.1074/jbc.M111.263442] [PMID: 21719706]
[53]
Kerres N, Steurer S, Schlager S, et al. Chemically induced degradation of the oncogenic transcription factor BCL6. Cell Rep 2017; 20(12): 2860-75.
[http://dx.doi.org/10.1016/j.celrep.2017.08.081] [PMID: 28930682]
[54]
Bayer and Arvinas unveil targeted protein degradation joint venture, Oerth bio 2019. Available from:. https://www.globenewswire.com/news-release/ 2019/10/01/1923054/0/en/Bayer-and-Arvinas-Unveil-Targeted-Protein-Degradation-Joint-Venture-Oerth-Bio.html
[55]
Wang P, Zhou J. Proteolysis targeting chimera (PROTAC): a paradigm-shifting approach in small molecule drug discovery. Curr Top Med Chem 2018; 18(16): 1354-6.
[http://dx.doi.org/10.2174/1568026618666181010101922] [PMID: 30306871]
[56]
Ghose AK, Herbertz T, Hudkins RL, Dorsey BD, Mallamo JP. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem Neurosci 2012; 3(1): 50-68.
[http://dx.doi.org/10.1021/cn200100h] [PMID: 22267984]
[57]
Arvinas to Present Preclinical Tau-Directed PROTAC® protein degrader data. Alzheimer’s Association International Conference | Arvinas 2019 July 18; New Haven, Connecticut, United States. Available from:. https://www.globenewswire.com/ news-release/2019/07/18/1884482/0/en/Arvinas-to-Present-Preclinical-Tau-Directed-PROTAC-Protein-Degrader-Data-at-Alzheimer-s-Association-International-Conference.html
[58]
Chamberlain PP, Hamann LG. Development of targeted protein degradation therapeutics. Nat Chem Biol 2019; 15(10): 937-44.
[http://dx.doi.org/10.1038/s41589-019-0362-y] [PMID: 31527835]
[59]
Zhang X, Crowley VM, Wucherpfennig TG, Dix MM, Cravatt BF. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat Chem Biol 2019; 15(7): 737-46.
[http://dx.doi.org/10.1038/s41589-019-0279-5] [PMID: 31209349]
[60]
Ottis P, Toure M, Cromm PM, Ko E, Gustafson JL, Crews CM. Assessing different E3 ligases for small molecule induced protein ubiquitination and degradation. ACS Chem Biol 2017; 12(10): 2570-8.
[http://dx.doi.org/10.1021/acschembio.7b00485] [PMID: 28767222]
[61]
Takahashi D, Moriyama J, Nakamura T, et al. AUTACs: cargo-specific degraders using selective autophagy. Mol Cell 2019; 76(5): 797-810.
[62]
Simonetta KR, Taygerly J, Boyle K, et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat Commun 2019; 10(1): 1402.
[http://dx.doi.org/10.1038/s41467-019-09358-9] [PMID: 30926793]

Rights & Permissions Print Cite
Article Metrics
16
3
© 2024 Bentham Science Publishers | Privacy Policy