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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Targeting Protein-Protein Interaction with Covalent Small-Molecule Inhibitors

Author(s): Bingbing Li, Deqin Rong and Yuanxiang Wang*

Volume 19, Issue 21, 2019

Page: [1872 - 1876] Pages: 5

DOI: 10.2174/1568026619666191011163410

Abstract

PPIs are involved in diverse biochemical events and perform their functions through the formation of protein-protein complexes or PPI networks. The large and flat interacting surfaces of PPIs make discovery of small-molecule modulators a challenging task. New strategies and more effective chemical technologies are needed to facilitate the development of PPIs small-molecule inhibitors. Covalent modification of a nucleophilic residue located proximally to the immediate vicinity of PPIs can overcome the disadvantages of large interacting surfaces and provides high-affinity inhibitors with increased duration of action and prolonged target modulation. On the other hand, covalent inhibitors that target non-conserved protein residues demonstrate improved selectivity over related protein family members. Herein, we highlight the latest progress of small-molecule covalent PPIs inhibitors and hope to shed light on future PPIs inhibitor design and development. The relevant challenges and opportunities are also discussed.

Keywords: Protein-protein interaction, covalent inhibitor, cysteine, lysine, methionine, GPCR.

« Previous Next »
[1]
Arkin, M.R.; Tang, Y.; Wells, J.A. Small-molecule inhibitors of protein-protein interactions: Progressing toward the reality. Chem. Biol., 2014, 21(9), 1102-1114.
[http://dx.doi.org/10.1016/j.chembiol.2014.09.001] [PMID: 25237857]
[2]
Lonsdale, R.; Ward, R.A. Structure-based design of targeted covalent inhibitors. Chem. Soc. Rev., 2018, 47(11), 3816-3830.
[http://dx.doi.org/10.1039/C7CS00220C] [PMID: 29620097]
[3]
Wang, Y.; Kaiser, C.E.; Frett, B.; Li, H.Y. Targeting mutant KRAS for anticancer therapeutics: A review of novel small molecule modulators. J. Med. Chem., 2013, 56(13), 5219-5230.
[http://dx.doi.org/10.1021/jm3017706] [PMID: 23566315]
[4]
Ye, N.; Zhou, J. KRAS - an evolving cancer target. Austin J. Cancer Clin. Res., 2014, 1(1), 1004.
[PMID: 27642639]
[5]
Ni, D.; Li, X.; He, X.; Zhang, H.; Zhang, J.; Lu, S. Drugging K-RasG12C through covalent inhibitors: Mission possible? Pharmacol. Ther., 2019, 202, 1-17.
[http://dx.doi.org/10.1016/j.pharmthera.2019.06.007] [PMID: 31233765]
[6]
Patricelli, M.P.; Janes, M.R.; Li, L.S.; Hansen, R.; Peters, U.; Kessler, L.V.; Chen, Y.; Kucharski, J.M.; Feng, J.; Ely, T.; Chen, J.H.; Firdaus, S.J.; Babbar, A.; Ren, P.; Liu, Y. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov., 2016, 6(3), 316-329.
[http://dx.doi.org/10.1158/2159-8290.CD-15-1105] [PMID: 26739882]
[7]
Janes, M.R.; Zhang, J.; Li, L.S.; Hansen, R.; Peters, U.; Guo, X.; Chen, Y.; Babbar, A.; Firdaus, S.J.; Darjania, L.; Feng, J.; Chen, J.H.; Li, S.; Li, S.; Long, Y.O.; Thach, C.; Liu, Y.; Zarieh, A.; Ely, T.; Kucharski, J.M.; Kessler, L.V.; Wu, T.; Yu, K.; Wang, Y.; Yao, Y.; Deng, X.; Zarrinkar, P.P.; Brehmer, D.; Dhanak, D.; Lorenzi, M.V.; Hu-Lowe, D.; Patricelli, M.P.; Ren, P.; Liu, Y. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell, 2018, 172(3), 578-589.e17.
[http://dx.doi.org/10.1016/j.cell.2018.01.006] [PMID: 29373830]
[8]
Fakih, M.; O’Neil, B.; Price, T.J.; Falchook, G.S.; Desai, J.; Kuo, J.; Govindan, R.; Rasmussen, E.; Morrow, P.K.H.; Ngang, J.; Henary, H.A.; Hong, D.S. Phase 1 study evaluating the safety, tolerability, pharmacokinetics and efficacy of AMG 510, a novel small molecule KRAS G12C inhibitor, in advanced solid tumors. J. Clin. Oncol., 2019, 37(Suppl. 15), 3003-3003.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.3003]
[9]
Mirati Therapeutic, Inc. Structure-Based Drug Discovery of MRTX1257, a Selective, Covalent KRAS G12C Inhibitor with Oral Activity in Animal Models of Cancer. https://www. mirati.com/wp-content/uploads/2018/12/KRAS-Poster-AACR-RAS.pdf
[10]
Cory, S.; Adams, J.M. The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer, 2002, 2(9), 647-656.
[http://dx.doi.org/10.1038/nrc883] [PMID: 12209154]
[11]
Wan, Y.; Dai, N.; Tang, Z.; Fang, H. Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents. Eur. J. Med. Chem., 2018, 146, 471-482.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.076] [PMID: 29407973]
[12]
Hird, A.W.; Tron, A.E. Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharmacol. Ther., 2019, 198, 59-67.
[http://dx.doi.org/10.1016/j.pharmthera.2019.02.007] [PMID: 30790641]
[13]
Friberg, A.; Vigil, D.; Zhao, B.; Daniels, R.N.; Burke, J.P.; Garcia-Barrantes, P.M.; Camper, D.; Chauder, B.A.; Lee, T.; Olejniczak, E.T.; Fesik, S.W. Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. J. Med. Chem., 2013, 56(1), 15-30.
[http://dx.doi.org/10.1021/jm301448p] [PMID: 23244564]
[14]
G.; Belmonte, M. A.; Aquila, B.; Chuaqui, C.; Hird, A. W.; Lamb, M. L.; Rawlins P. B.; Su, N.; Tentarelli, S.; Grimster, N. P.; Su, Q. Inhibition of MCL-1 through covalent modification of a noncatalytic lysine side chain. Nat. Chem. Biol., 2016, 12, 931-936.
[http://dx.doi.org/10.1038/nchembio.2174]
[15]
Doroshow, D.B.; Eder, J.P.; LoRusso, P.M. BET inhibitors: a novel epigenetic approach. Ann. Oncol., 2017, 28(8), 1776-1787.
[http://dx.doi.org/10.1093/annonc/mdx157] [PMID: 28838216]
[16]
Liu, Z.; Wang, P.; Chen, H.; Wold, E.A.; Tian, B.; Brasier, A.R.; Zhou, J. Drug discovery targeting bromodomain-containing protein 4. J. Med. Chem., 2017, 60(11), 4533-4558.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01761] [PMID: 28195723]
[17]
Wang, P.; Zhou, J. Proteolysis Targeting chimera (PROTAC): A paradigm-shifting approach in small molecule drug discovery. Curr. Top. Med. Chem., 2018, 18(16), 1354-1356.
[http://dx.doi.org/10.2174/1568026618666181010101922] [PMID: 30306871]
[18]
Alferiev, I.S.; Hinson, J.T.; Ogle, M.; Breuer, E.; Levy, R.J. High reactivity of alkyl sulfides towards epoxides under conditions of collagen fixation--a convenient approach to 2-amino-4-butyrolactones. Biomaterials, 2001, 22(18), 2501-2506.
[http://dx.doi.org/10.1016/S0142-9612(00)00440-3] [PMID: 11516082]
[19]
Liu, S. Preparation of heterocyclic compounds as bromodomain inhibitors. Resverlogix Corp, WO, 2014, 2014096965, A2.
[20]
Kharenko, O.A.; Patel, R.G.; Brown, S.D.; Calosing, C.; White, A.; Lakshminarasimhan, D.; Suto, R.K.; Duffy, B.C.; Kitchen, D.B.; McLure, K.G.; Hansen, H.C.; van der Horst, E.H.; Young, P.R. Patel, R. G.; David Brown, S.; Calosing, C.; White, A.; Lakshminarasimhan, D.; Suto, R. K.; Duffy, B. C.;Kitchen, D.B.; McLure, K. G.; Hansen, H.C.; van der Horst, E. H.; Young,P. R. Design and characterization of novel covalent bromodomain and extra-terminal domain (BET) inhibitors targeting a methionine. J. Med. Chem., 2018, 61(18), 8202-8211.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00666] [PMID: 30165024]

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