Fragment-based Drug Discovery Successful Contributions to Current Pharmacotherapeutic Agents Arsenal against Aggressive Cancers: A Mini-Review


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After a decade of approval of the drug vemurafenib in 2011, the hopeless scenario imposed by some severe cancer types has been mitigated by the magic bullets developed through fragment-based drug discovery. Moreover, this recent approach to medicinal chemistry has been successfully practiced by academic laboratories and pharmaceutical industry workflows focused on drug design with an enhanced profile for chemotherapy of aggressive tumors. This mini-review highlights the successes achieved by these research campaigns in the fruitful field of the molecular fragment paradigm that resulted in the approval of six new anticancer drugs in the last decade (2011-2021), as well as several promising clinical candidates. It is a particularly encouraging opportunity for other researchers who want to become aware of the applicability and potency of this new paradigm applied to the design and development of powerful molecular weapons in the constant war against these merciless scourges of humanity.

Sobre autores

Leandro Santos

Laboratory of Molecular Modeling and Computer Simulation / MolMod-CS (D311-F), Institute of Chemistry,, Federal University of Alfenas / UNIFAL-MG

Autor responsável pela correspondência
Email: info@benthamscience.net

Nelson da Silveira

Laboratory of Molecular Modeling and Computer Simulation / MolMod-CS (D311-F), Institute of Chemistry, Federal University of Alfenas / UNIFAL-MG

Email: info@benthamscience.net

Bibliografia

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249. doi: 10.3322/caac.21660 PMID: 33538338
  2. Ugai, T.; Sasamoto, N.; Lee, H.Y.; Ando, M.; Song, M.; Tamimi, R.M.; Kawachi, I.; Campbell, P.T.; Giovannucci, E.L.; Weiderpass, E.; Rebbeck, T.R.; Ogino, S. Is early-onset cancer an emerging global epidemic? Current evidence and future implications. Nat. Rev. Clin. Oncol., 2022, 19(10), 656-673. doi: 10.1038/s41571-022-00672-8 PMID: 36068272
  3. Chen, W.; Sun, Z.; Lu, L. Targeted engineering of medicinal chemistry for cancer therapy: Recent advances and perspectives. Angew. Chem. Int. Ed., 2021, 60(11), 5626-5643. doi: 10.1002/anie.201914511 PMID: 32096328
  4. Stine, Z.E.; Schug, Z.T.; Salvino, J.M.; Dang, C.V. Targeting cancer metabolism in the era of precision oncology. Nat. Rev. Drug Discov., 2022, 21(2), 141-162. doi: 10.1038/s41573-021-00339-6 PMID: 34862480
  5. Pedreira, J.G.B.; Franco, L.S.; Barreiro, E.J. Chemical intuition in drug design and discovery. Curr. Top. Med. Chem., 2019, 19(19), 1679-1693. doi: 10.2174/1568026619666190620144142 PMID: 31258088
  6. Fischer, E. Einfluss der configuration auf die wirkung der enzima. Ber. Dtsch. Chem. Ges., 1894, 27(3), 2985-2993. doi: 10.1002/cber.18940270364
  7. Ehrlich, P. Chemotherapeutics: Scientific principles, methods and results. Lancet, 1913, 182, 445-451. doi: 10.1016/S0140-6736(01)38705-6
  8. Li, Q.; Kang, C. Perspectives on fragment-based drug discovery: A strategy applicable to diverse targets. Curr. Top. Med. Chem., 2021, 21(13), 1099-1112. doi: 10.2174/1568026621666210804115700 PMID: 34348623
  9. Bon, M.; Bilsland, A.; Bower, J.; McAulay, K. Fragment‐based drug discovery—the importance of high‐quality molecule libraries. Mol. Oncol., 2022, 16(21), 3761-3777. doi: 10.1002/1878-0261.13277 PMID: 35749608
  10. de Esch, I.J.P.; Erlanson, D.A.; Jahnke, W.; Johnson, C.N.; Walsh, L. Fragment-to-lead medicinal chemistry publications in 2020. J. Med. Chem., 2022, 65(1), 84-99. doi: 10.1021/acs.jmedchem.1c01803 PMID: 34928151
  11. Erlanson, D. Practical fragments. Available From: https://practicalfragments.blogspot.com/2022/11/fragments-in-clinic-2022-edition.html (accessed December 20, 2022).
  12. Rapp, U.R.; Goldsborough, M.D.; Mark, G.E.; Bonner, T.I.; Groffen, J.; Reynolds, F.H., Jr; Stephenson, J.R. Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc. Natl. Acad. Sci. USA, 1983, 80(14), 4218-4222.https://www.pnas.org/doi/pdf/10.1073/pnas.80.14.4218 doi: 10.1073/pnas.80.14.4218 PMID: 6308607
  13. Beck, T.W.; Huleihel, M.; Gunnell, M.; Bonner, T.I.; Rapp, U.R. The complete coding sequence of the human A- raf -1 oncogene and transforming activity of a human A- raf carrying retrovirus. Nucleic Acids Res., 1987, 15(2), 595-609. doi: 10.1093/nar/15.2.595 PMID: 3029685
  14. Ikawa, S.; Fukui, M.; Ueyama, Y.; Tamaoki, N.; Yamamoto, T.; Toyoshima, K. B-raf, a new member of the raf family, is activated by DNA rearrangement. Mol. Cell. Biol., 1988, 8(6), 2651-2654. doi: 10.1128/mcb.8.6.2651-2654.1988 PMID: 3043188
  15. Holderfield, M.; Deuker, M.M.; McCormick, F.; McMahon, M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat. Rev. Cancer, 2014, 14(7), 455-467. doi: 10.1038/nrc3760 PMID: 24957944
  16. Davies, H.; Bignell, G.R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M.J.; Bottomley, W.; Davis, N.; Dicks, E.; Ewing, R.; Floyd, Y.; Gray, K.; Hall, S.; Hawes, R.; Hughes, J.; Kosmidou, V.; Menzies, A.; Mould, C.; Parker, A.; Stevens, C.; Watt, S.; Hooper, S.; Wilson, R.; Jayatilake, H.; Gusterson, B.A.; Cooper, C.; Shipley, J.; Hargrave, D.; Pritchard-Jones, K.; Maitland, N.; Chenevix-Trench, G.; Riggins, G.J.; Bigner, D.D.; Palmieri, G.; Cossu, A.; Flanagan, A.; Nicholson, A.; Ho, J.W.C.; Leung, S.Y.; Yuen, S.T.; Weber, B.L.; Seigler, H.F.; Darrow, T.L.; Paterson, H.; Marais, R.; Marshall, C.J.; Wooster, R.; Stratton, M.R.; Futreal, P.A. Mutations of the BRAF gene in human cancer. Nature, 2002, 417(6892), 949-954. doi: 10.1038/nature00766 PMID: 12068308
  17. Schirripa, M.; Biason, P.; Lonardi, S.; Pella, N.; Pino, M.S.; Urbano, F.; Antoniotti, C.; Cremolini, C.; Corallo, S.; Pietrantonio, F.; Gelsomino, F.; Cascinu, S.; Orlandi, A.; Munari, G.; Malapelle, U.; Saggio, S.; Fontanini, G.; Rugge, M.; Mescoli, C.; Lazzi, S.; Reggiani Bonetti, L.; Lanza, G.; Dei Tos, A.P.; De Maglio, G.; Martini, M.; Bergamo, F.; Zagonel, V.; Loupakis, F.; Fassan, M. Class 1, 2, and 3 BRAF-mutated metastatic colorectal cancer: A detailed clinical, pathologic, and molecular characterization. Clin. Cancer Res., 2019, 25(13), 3954-3961. doi: 10.1158/1078-0432.CCR-19-0311 PMID: 30967421
  18. Śmiech, M.; Leszczyński, P.; Kono, H.; Wardell, C.; Taniguchi, H. Emerging BRAF mutations in cancer progression and their possible effects on transcriptional networks. Genes, 2020, 11(11), 1342. doi: 10.3390/genes11111342 PMID: 33198372
  19. Ko, J.S. The immunology of melanoma. Clin. Lab. Med., 2017, 37(3), 449-471. doi: 10.1016/j.cll.2017.06.001 PMID: 28802495
  20. Kumar, A.; Mandiyan, V.; Suzuki, Y.; Zhang, C.; Rice, J.; Tsai, J.; Artis, D.R.; Ibrahim, P.; Bremer, R. Crystal structures of proto-oncogene kinase Pim1: A target of aberrant somatic hypermutations in diffuse large cell lymphoma. J. Mol. Biol., 2005, 348(1), 183-193. doi: 10.1016/j.jmb.2005.02.039 PMID: 15808862
  21. Tsai, J.; Lee, J.T.; Wang, W.; Zhang, J.; Cho, H.; Mamo, S.; Bremer, R.; Gillette, S.; Kong, J.; Haass, N.K.; Sproesser, K.; Li, L.; Smalley, K.S.M.; Fong, D.; Zhu, Y.L.; Marimuthu, A.; Nguyen, H.; Lam, B.; Liu, J.; Cheung, I.; Rice, J.; Suzuki, Y.; Luu, C.; Settachatgul, C.; Shellooe, R.; Cantwell, J.; Kim, S.H.; Schlessinger, J.; Zhang, K.Y.J.; West, B.L.; Powell, B.; Habets, G.; Zhang, C.; Ibrahim, P.N.; Hirth, P.; Artis, D.R.; Herlyn, M.; Bollag, G. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. USA, 2008, 105(8), 3041-3046. doi: 10.1073/pnas.0711741105 PMID: 18287029
  22. Bollag, G.; Hirth, P.; Tsai, J.; Zhang, J.; Ibrahim, P.N.; Cho, H.; Spevak, W.; Zhang, C.; Zhang, Y.; Habets, G.; Burton, E.A.; Wong, B.; Tsang, G.; West, B.L.; Powell, B.; Shellooe, R.; Marimuthu, A.; Nguyen, H.; Zhang, K.Y.J.; Artis, D.R.; Schlessinger, J.; Su, F.; Higgins, B.; Iyer, R.; D'Andrea, K.; Koehler, A.; Stumm, M.; Lin, P.S.; Lee, R.J.; Grippo, J.; Puzanov, I.; Kim, K.B.; Ribas, A.; McArthur, G.A.; Sosman, J.A.; Chapman, P.B.; Flaherty, K.T.; Xu, X.; Nathanson, K.L.; Nolop, K. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 2010, 467(7315), 596-599. doi: 10.1038/nature09454 PMID: 20823850
  23. Flaherty, K.T.; Yasothan, U.; Kirkpatrick, P. Vemurafenib. Nat. Rev. Drug Discov., 2011, 10(11), 811-812. doi: 10.1038/nrd3579 PMID: 22037033
  24. Bollag, G.; Tsai, J.; Zhang, J.; Zhang, C.; Ibrahim, P.; Nolop, K.; Hirth, P. Vemurafenib: The first drug approved for BRAF-mutant cancer. Nat. Rev. Drug Discov., 2012, 11(11), 873-886. doi: 10.1038/nrd3847 PMID: 23060265
  25. Brown, D.G.; Wobst, H.J. A decade of FDA-approved drugs (2010-2019): Trends and future directions. J. Med. Chem., 2021, 64(5), 2312-2338. doi: 10.1021/acs.jmedchem.0c01516 PMID: 33617254
  26. Muchmore, S.W.; Sattler, M.; Liang, H.; Meadows, R.P.; Harlan, J.E.; Yoon, H.S.; Nettesheim, D.; Chang, B.S.; Thompson, C.B.; Wong, S.L.; Ng, S.C.; Fesik, S.W. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature, 1996, 381(6580), 335-341. doi: 10.1038/381335a0 PMID: 8692274
  27. Oltersdorf, T.; Elmore, S.W.; Shoemaker, A.R.; Armstrong, R.C.; Augeri, D.J.; Belli, B.A.; Bruncko, M.; Deckwerth, T.L.; Dinges, J.; Hajduk, P.J.; Joseph, M.K.; Kitada, S.; Korsmeyer, S.J.; Kunzer, A.R.; Letai, A.; Li, C.; Mitten, M.J.; Nettesheim, D.G.; Ng, S.; Nimmer, P.M.; O'Connor, J.M.; Oleksijew, A.; Petros, A.M.; Reed, J.C.; Shen, W.; Tahir, S.K.; Thompson, C.B.; Tomaselli, K.J.; Wang, B.; Wendt, M.D.; Zhang, H.; Fesik, S.W.; Rosenberg, S.H. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 2005, 435(7042), 677-681. doi: 10.1038/nature03579 PMID: 15902208
  28. Shoemaker, A.R.; Oleksijew, A.; Bauch, J.; Belli, B.A.; Borre, T.; Bruncko, M.; Deckwirth, T.; Frost, D.J.; Jarvis, K.; Joseph, M.K.; Marsh, K.; McClellan, W.; Nellans, H.; Ng, S.; Nimmer, P.; O'Connor, J.M.; Oltersdorf, T.; Qing, W.; Shen, W.; Stavropoulos, J.; Tahir, S.K.; Wang, B.; Warner, R.; Zhang, H.; Fesik, S.W.; Rosenberg, S.H.; Elmore, S.W. A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo. Cancer Res., 2006, 66(17), 8731-8739. doi: 10.1158/0008-5472.CAN-06-0367 PMID: 16951189
  29. Tse, C.; Shoemaker, A.R.; Adickes, J.; Anderson, M.G.; Chen, J.; Jin, S.; Johnson, E.F.; Marsh, K.C.; Mitten, M.J.; Nimmer, P.; Roberts, L.; Tahir, S.K.; Xiao, Y.; Yang, X.; Zhang, H.; Fesik, S.; Rosenberg, S.H.; Elmore, S.W. ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res., 2008, 68(9), 3421-3428. doi: 10.1158/0008-5472.CAN-07-5836 PMID: 18451170
  30. Ackler, S.; Xiao, Y.; Mitten, M.J.; Foster, K.; Oleksijew, A.; Refici, M.; Schlessinger, S.; Wang, B.; Chemburkar, S.R.; Bauch, J.; Tse, C.; Frost, D.J.; Fesik, S.W.; Rosenberg, S.H.; Elmore, S.W.; Shoemaker, A.R. ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol. Cancer Ther., 2008, 7(10), 3265-3274. doi: 10.1158/1535-7163.MCT-08-0268 PMID: 18852130
  31. Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; Huang, D.C.S.; Hymowitz, S.G.; Jin, S.; Khaw, S.L.; Kovar, P.J.; Lam, L.T.; Lee, J.; Maecker, H.L.; Marsh, K.C.; Mason, K.D.; Mitten, M.J.; Nimmer, P.M.; Oleksijew, A.; Park, C.H.; Park, C.M.; Phillips, D.C.; Roberts, A.W.; Sampath, D.; Seymour, J.F.; Smith, M.L.; Sullivan, G.M.; Tahir, S.K.; Tse, C.; Wendt, M.D.; Xiao, Y.; Xue, J.C.; Zhang, H.; Humerickhouse, R.A.; Rosenberg, S.H.; Elmore, S.W. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med., 2013, 19(2), 202-208. doi: 10.1038/nm.3048 PMID: 23291630
  32. Cang, S.; Iragavarapu, C.; Savooji, J.; Song, Y.; Liu, D. ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J. Hematol. Oncol., 2015, 8(1), 129. doi: 10.1186/s13045-015-0224-3 PMID: 26589495
  33. Leverson, J.D.; Sampath, D.; Souers, A.J.; Rosenberg, S.H.; Fairbrother, W.J.; Amiot, M.; Konopleva, M.; Letai, A. Found in translation: How preclinical research is guiding the clinical development of the BCL2-selective inhibitor venetoclax. Cancer Discov., 2017, 7(12), 1376-1393. doi: 10.1158/2159-8290.CD-17-0797 PMID: 29146569
  34. Erlanson, D.A.; Fesik, S.W.; Hubbard, R.E.; Jahnke, W.; Jhoti, H. Twenty years on: The impact of fragments on drug discovery. Nat. Rev. Drug Discov., 2016, 15(9), 605-619. doi: 10.1038/nrd.2016.109 PMID: 27417849
  35. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26. doi: 10.1016/S0169-409X(00)00129-0 PMID: 11259830
  36. Siefker-Radtke, A.O.; Necchi, A.; Park, S.H.; García-Donas, J.; Huddart, R.A.; Burgess, E.F.; Fleming, M.T.; Rezazadeh Kalebasty, A.; Mellado, B.; Varlamov, S.; Joshi, M.; Duran, I.; Tagawa, S.T.; Zakharia, Y.; Akapame, S.; Santiago-Walker, A.E.; Monga, M.; O'Hagan, A.; Loriot, Y.; Necchi, A.; Loriot, Y.; Park, S.H.; Tagawa, S.; Flechon, A.; Alexeev, B.; Varlamov, S.; Huddart, R.; Burgess, E.; Rezazadeh, A.; Siefker-Radtke, A.; Vano, Y.; Gasparro, D.; Hamzaj, A.; Kopyltsov, E.; Gracia Donas, J.; Mellado, B.; Parikh, O.; Schatteman, P.; Culine, S.; Houédé, N.; Zanetta, S.; Facchini, G.; Scagliotti, G.; Schinzari, G.; Lee, J.L.; Shkolnik, M.; Fleming, M.; Joshi, M.; O'Donnell, P.; Stöger, H.; Decaestecker, K.; Dirix, L.; Machiels, J.P.; Borchiellini, D.; Delva, R.; Rolland, F.; Hadaschik, B.; Retz, M.; Rosenbaum, E.; Basso, U.; Mosca, A.; Lee, H.J.; Shin, D.B.; Cebotaru, C.; Duran, I.; Moreno, V.; Perez Gracia, J.L.; Pinto, A.; Su, W-P.; Wang, S-S.; Hainsworth, J.; Schnadig, I.; Srinivas, S.; Vogelzang, N.; Loidl, W.; Meran, J.; Gross Goupil, M.; Joly, F.; Imkamp, F.; Klotz, T.; Krege, S.; May, M.; Schultze-Seemann, W.; Strauss, A.; Zimmermann, U.; Keizman, D.; Peer, A.; Sella, A.; Berardi, R.; De Giorgi, U.; Sternberg, C.N.; Rha, S.Y.; Bulat, I.; Izmailov, A.; Matveev, V.; Vladimirov, V.; Carles, J.; Font, A.; Saez, M.; Syndikus, I.; Tarver, K.; Appleman, L.; Burke, J.; Dawson, N.; Jain, S.; Zakharia, Y. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol., 2022, 23(2), 248-258. doi: 10.1016/S1470-2045(21)00660-4 PMID: 35030333
  37. Krook, M.A.; Reeser, J.W.; Ernst, G.; Barker, H.; Wilberding, M.; Li, G.; Chen, H.Z.; Roychowdhury, S. Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. Br. J. Cancer, 2021, 124(5), 880-892. doi: 10.1038/s41416-020-01157-0 PMID: 33268819
  38. Peng, J.; Sridhar, S.; Siefker-Radtke, A.O.; Selvarajah, S.; Jiang, D.M. Targeting the FGFR pathway in urothelial carcinoma: The future is now. Curr. Treat. Options Oncol., 2022, 23(9), 1269-1287. doi: 10.1007/s11864-022-01009-4 PMID: 35962938
  39. Squires, M.; Ward, G.; Saxty, G.; Berdini, V.; Cleasby, A.; King, P.; Angibaud, P.; Perera, T.; Fazal, L.; Ross, D.; Jones, C.G.; Madin, A.; Benning, R.K.; Vickerstaffe, E.; O'Brien, A.; Frederickson, M.; Reader, M.; Hamlett, C.; Batey, M.A.; Rich, S.; Carr, M.; Miller, D.; Feltell, R.; Thiru, A.; Bethell, S.; Devine, L.A.; Graham, B.L.; Pike, A.; Cosme, J.; Lewis, E.J.; Freyne, E.; Lyons, J.; Irving, J.; Murray, C.; Newell, D.R.; Thompson, N.T. Potent, selective inhibitors of fibroblast growth factor receptor define fibroblast growth factor dependence in preclinical cancer models. Mol. Cancer Ther., 2011, 10(9), 1542-1552. doi: 10.1158/1535-7163.MCT-11-0426 PMID: 21764904
  40. Murray, C.W.; Newell, D.R.; Angibaud, P. A successful collaboration between academia, biotech and pharma led to discovery of erdafitinib, a selective FGFR inhibitor recently approved by the FDA. MedChemComm, 2019, 10(9), 1509-1511. doi: 10.1039/C9MD90044F
  41. El Newahie, A.M.S.; Ismail, N.S.M.; Abou El Ella, D.A.; Abouzid, K.A.M. Quinoxaline-based scaffolds targeting tyrosine kinases and their potential anticancer activity: Quinoxaline-based scaffolds targeting tyrosine kinases. Arch. Pharm., 2016, 349(5), 309-326. doi: 10.1002/ardp.201500468 PMID: 27062086
  42. Kumar, V.; Kaur, N.; Sahu, S. Role of tyrosine kinases and their inhibitors in cancer therapy: A comprehensive review. Curr. Med. Chem., 2022, 30(13), 1464-1481. doi: 10.2174/0929867329666220727122952
  43. Rees, D.C. Medicines for millions of patients. RSC Med. Chem., 2022, 13(1), 7-12. doi: 10.1039/D1MD00279A PMID: 35211673
  44. Nishina, T.; Takahashi, S.; Iwasawa, R.; Noguchi, H.; Aoki, M.; Doi, T. Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Invest. New Drugs, 2018, 36(3), 424-434. doi: 10.1007/s10637-017-0514-4 PMID: 28965185
  45. Perera, T.P.S.; Jovcheva, E.; Mevellec, L.; Vialard, J.; De Lange, D.; Verhulst, T.; Paulussen, C.; Van De Ven, K.; King, P.; Freyne, E.; Rees, D.C.; Squires, M.; Saxty, G.; Page, M.; Murray, C.W.; Gilissen, R.; Ward, G.; Thompson, N.T.; Newell, D.R.; Cheng, N.; Xie, L.; Yang, J.; Platero, S.J.; Karkera, J.D.; Moy, C.; Angibaud, P.; Laquerre, S.; Lorenzi, M.V. Discovery and pharmacological characterization of JNJ-42756493 (erdafitinib), a functionally selective small-molecule FGFR family inhibitor. Mol. Cancer Ther., 2017, 16(6), 1010-1020. doi: 10.1158/1535-7163.MCT-16-0589 PMID: 28341788
  46. Bansal, P.; Dwivedi, D.K.; Hatwal, D.; Sharma, P.; Gupta, V.; Goyal, S.; Maithani, M. Erdafitinib as a novel and advanced treatment strategy of metastatic urothelial carcinoma. Anticancer. Agents Med. Chem., 2021, 21(18), 2478-2486. doi: 10.2174/1871520621666210121093852 PMID: 33475078
  47. Spierenburg, G.; van der Heijden, L.; van Langevelde, K.; Szuhai, K.; Bovée, J.V.G.M.; van de Sande, M.A.J.; Gelderblom, H. Tenosynovial giant cell tumors (TGCT): Molecular biology, drug targets and non-surgical pharmacological approaches. Expert Opin. Ther. Targets, 2022, 26(4), 333-345. doi: 10.1080/14728222.2022.2067040 PMID: 35443852
  48. Dupont, C.A.; Riegel, K.; Pompaiah, M.; Juhl, H.; Rajalingam, K. Druggable genome and precision medicine in cancer: current challenges. FEBS J., 2021, 288(21), 6142-6158. doi: 10.1111/febs.15788 PMID: 33626231
  49. Wen, J.; Wang, S.; Guo, R.; Liu, D. CSF1R inhibitors are emerging immunotherapeutic drugs for cancer treatment. Eur. J. Med. Chem., 2023, 245(Pt 1), 114884. doi: 10.1016/j.ejmech.2022.114884 PMID: 36335744
  50. Palmerini, E.; Staals, E.L. Treatment updates on tenosynovial giant cell tumor. Curr. Opin. Oncol., 2022, 34(4), 322-327. doi: 10.1097/CCO.0000000000000853 PMID: 35837703
  51. Zhang, C.; Ibrahim, P.N.; Zhang, J.; Burton, E.A.; Habets, G.; Zhang, Y.; Powell, B.; West, B.L.; Matusow, B.; Tsang, G.; Shellooe, R.; Carias, H.; Nguyen, H.; Marimuthu, A.; Zhang, K.Y.J.; Oh, A.; Bremer, R.; Hurt, C.R.; Artis, D.R.; Wu, G.; Nespi, M.; Spevak, W.; Lin, P.; Nolop, K.; Hirth, P.; Tesch, G.H.; Bollag, G. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor. Proc. Natl. Acad. Sci. USA, 2013, 110(14), 5689-5694. doi: 10.1073/pnas.1219457110 PMID: 23493555
  52. Tap, W.D.; Wainberg, Z.A.; Anthony, S.P.; Ibrahim, P.N.; Zhang, C.; Healey, J.H.; Chmielowski, B.; Staddon, A.P.; Cohn, A.L.; Shapiro, G.I.; Keedy, V.L.; Singh, A.S.; Puzanov, I.; Kwak, E.L.; Wagner, A.J.; Von Hoff, D.D.; Weiss, G.J.; Ramanathan, R.K.; Zhang, J.; Habets, G.; Zhang, Y.; Burton, E.A.; Visor, G.; Sanftner, L.; Severson, P.; Nguyen, H.; Kim, M.J.; Marimuthu, A.; Tsang, G.; Shellooe, R.; Gee, C.; West, B.L.; Hirth, P.; Nolop, K.; van de Rijn, M.; Hsu, H.H.; Peterfy, C.; Lin, P.S.; Tong-Starksen, S.; Bollag, G. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N. Engl. J. Med., 2015, 373(5), 428-437. doi: 10.1056/NEJMoa1411366 PMID: 26222558
  53. Alsayadi, Y.M.M.A.; Chawla, P.A. Prospects of treating tenosynovial giant cell tumor through pexidartinib: A review. Anticancer. Agents Med. Chem., 2021, 21(12), 1510-1519. doi: 10.2174/1871520620999201102123555 PMID: 33143617
  54. Benner, B.; Good, L.; Quiroga, D.; Schultz, T.E.; Kassem, M.; Carson, W.E.; Cherian, M.A.; Sardesai, S.; Wesolowski, R. Pexidartinib, a novel small molecule CSF-1R inhibitor in use for tenosynovial giant cell tumor: A systematic review of pre-clinical and clinical development. Drug Des. Devel. Ther., 2020, 14, 1693-1704. doi: 10.2147/DDDT.S253232 PMID: 32440095
  55. Liang, X.; Wu, P.; Yang, Q.; Xie, Y.; He, C.; Yin, L.; Yin, Z.; Yue, G.; Zou, Y.; Li, L.; Song, X.; Lv, C.; Zhang, W.; Jing, B. An update of new small-molecule anticancer drugs approved from 2015 to 2020. Eur. J. Med. Chem., 2021, 220, 113473. doi: 10.1016/j.ejmech.2021.113473 PMID: 33906047
  56. Rio-Vilariño, A.; del Puerto-Nevado, L.; García-Foncillas, J.; Cebrián, A. Ras family of small GTPases in CRC: New perspectives for overcoming drug resistance. Cancers (Basel), 2021, 13(15), 3757. doi: 10.3390/cancers13153757 PMID: 34359657
  57. Sheffels, E.; Kortum, R.L. The role of wild-type RAS in oncogenic RAS transformation. Genes, 2021, 12(5), 662. doi: 10.3390/genes12050662
  58. Erlanson, D.A.; Webster, K.R. Targeting mutant KRAS. Curr. Opin. Chem. Biol., 2021, 62, 101-108. doi: 10.1016/j.cbpa.2021.02.010 PMID: 33838397
  59. Li, H-Y.; Qi, W-L.; Wang, Y-X. Covalent inhibitor targets KRasG12C: A new paradigm for drugging the undruggable and challenges ahead. Genes Dis., 2021. Epub ahead of print doi: 10.1016/j.gendis.2021.08.011
  60. Ostrem, J.M.; Peters, U.; Sos, M.L.; Wells, J.A.; Shokat, K.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013, 503(7477), 548-551. doi: 10.1038/nature12796 PMID: 24256730
  61. 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. doi: 10.1016/j.cell.2018.01.006 PMID: 29373830
  62. Shin, Y.; Jeong, J.W.; Wurz, R.P.; Achanta, P.; Arvedson, T.; Bartberger, M.D.; Campuzano, I.D.G.; Fucini, R.; Hansen, S.K.; Ingersoll, J.; Iwig, J.S.; Lipford, J.R.; Ma, V.; Kopecky, D.J.; McCarter, J.; San Miguel, T.; Mohr, C.; Sabet, S.; Saiki, A.Y.; Sawayama, A.; Sethofer, S.; Tegley, C.M.; Volak, L.P.; Yang, K.; Lanman, B.A.; Erlanson, D.A.; Cee, V.J. Discovery of N -(1-Acryloylazetidin-3-yl)-2-(1 H -indol-1-yl)acetamides as Covalent Inhibitors of KRAS G12C. ACS Med. Chem. Lett., 2019, 10(9), 1302-1308. doi: 10.1021/acsmedchemlett.9b00258 PMID: 31531201
  63. Lanman, B.A.; Allen, J.R.; Allen, J.G.; Amegadzie, A.K.; Ashton, K.S.; Booker, S.K.; Chen, J.J.; Chen, N.; Frohn, M.J.; Goodman, G.; Kopecky, D.J.; Liu, L.; Lopez, P.; Low, J.D.; Ma, V.; Minatti, A.E.; Nguyen, T.T.; Nishimura, N.; Pickrell, A.J.; Reed, A.B.; Shin, Y.; Siegmund, A.C.; Tamayo, N.A.; Tegley, C.M.; Walton, M.C.; Wang, H.L.; Wurz, R.P.; Xue, M.; Yang, K.C.; Achanta, P.; Bartberger, M.D.; Canon, J.; Hollis, L.S.; McCarter, J.D.; Mohr, C.; Rex, K.; Saiki, A.Y.; San, M.T.; Volak, L.P.; Wang, K.H.; Whittington, D.A.; Zech, S.G.; Lipford, J.R.; Cee, V.J. Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors. J. Med. Chem., 2020, 63(1), 52-65. doi: 10.1021/acs.jmedchem.9b01180 PMID: 31820981
  64. Blair, H.A. Sotorasib: First Approval. Drugs, 2021, 81(13), 1573-1579. doi: 10.1007/s40265-021-01574-2 PMID: 34357500
  65. Deeks, E.D. Asciminib: First Approval. Drugs, 2022, 82(2), 219-226. doi: 10.1007/s40265-021-01662-3 PMID: 35041175
  66. Schoepfer, J.; Jahnke, W.; Berellini, G.; Buonamici, S.; Cotesta, S.; Cowan-Jacob, S.W.; Dodd, S.; Drueckes, P.; Fabbro, D.; Gabriel, T.; Groell, J.M.; Grotzfeld, R.M.; Hassan, A.Q.; Henry, C.; Iyer, V.; Jones, D.; Lombardo, F.; Loo, A.; Manley, P.W.; Pellé, X.; Rummel, G.; Salem, B.; Warmuth, M.; Wylie, A.A.; Zoller, T.; Marzinzik, A.L.; Furet, P. Discovery of asciminib(ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J. Med. Chem., 2018, 61(18), 8120-8135. doi: 10.1021/acs.jmedchem.8b01040 PMID: 30137981
  67. Cohen, P.; Cross, D.; Jänne, P.A. Kinase drug discovery 20 years after imatinib: Progress and future directions. Nat. Rev. Drug Discov., 2021, 20(7), 551-569. doi: 10.1038/s41573-021-00195-4 PMID: 34002056
  68. Réa, D.; Hughes, T.P. Development of asciminib, a novel allosteric inhibitor of BCR-ABL1. Crit. Rev. Oncol. Hematol., 2022, 171, 103580. doi: 10.1016/j.critrevonc.2022.103580 PMID: 35021069
  69. Nagar, B.; Hantschel, O.; Young, M.A.; Scheffzek, K.; Veach, D.; Bornmann, W.; Clarkson, B.; Superti-Furga, G.; Kuriyan, J. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell, 2003, 112(6), 859-871. doi: 10.1016/S0092-8674(03)00194-6 PMID: 12654251
  70. Hantschel, O.; Nagar, B.; Guettler, S.; Kretzschmar, J.; Dorey, K.; Kuriyan, J.; Superti-Furga, G. A myristoyl/phosphotyrosine switch regulates c-Abl. Cell, 2003, 112(6), 845-857. doi: 10.1016/S0092-8674(03)00191-0 PMID: 12654250
  71. Adrián, F.J.; Ding, Q.; Sim, T.; Velentza, A.; Sloan, C.; Liu, Y.; Zhang, G.; Hur, W.; Ding, S.; Manley, P.; Mestan, J.; Fabbro, D.; Gray, N.S. Allosteric inhibitors of Bcr-abl–dependent cell proliferation. Nat. Chem. Biol., 2006, 2(2), 95-102. doi: 10.1038/nchembio760 PMID: 16415863
  72. Schiffer, C.A. Asciminib for CML: Same target, new arrow. Blood, 2021, 138(21), 2009-2010. doi: 10.1182/blood.2021013257 PMID: 34821938
  73. Addie, M.; Ballard, P.; Buttar, D.; Crafter, C.; Currie, G.; Davies, B.R.; Debreczeni, J.; Dry, H.; Dudley, P.; Greenwood, R.; Johnson, P.D.; Kettle, J.G.; Lane, C.; Lamont, G.; Leach, A.; Luke, R.W.A.; Morris, J.; Ogilvie, D.; Page, K.; Pass, M.; Pearson, S.; Ruston, L. Discovery of 4-Amino- N -(1 S)-1-(4-chlorophenyl)-3-hydroxypropyl-1-(7 H -pyrrolo2,3- dpyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases. J. Med. Chem., 2013, 56(5), 2059-2073. doi: 10.1021/jm301762v PMID: 23394218
  74. Siu, K.T.; Ramachandran, J.; Yee, A.J.; Eda, H.; Santo, L.; Panaroni, C.; Mertz, J.A.; Sims, R.J., III; Cooper, M.R.; Raje, N. Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma. Leukemia, 2017, 31(8), 1760-1769. doi: 10.1038/leu.2016.355 PMID: 27890933
  75. Gehling, V.S.; Hewitt, M.C.; Vaswani, R.G.; Leblanc, Y.; Côté, A.; Nasveschuk, C.G.; Taylor, A.M.; Harmange, J.C.; Audia, J.E.; Pardo, E.; Joshi, S.; Sandy, P.; Mertz, J.A.; Sims, R.J., III; Bergeron, L.; Bryant, B.M.; Bellon, S.; Poy, F.; Jayaram, H.; Sankaranarayanan, R.; Yellapantula, S.; Bangalore Srinivasamurthy, N.; Birudukota, S.; Albrecht, B.K. Discovery, design, and optimization of isoxazole azepine BET inhibitors. ACS Med. Chem. Lett., 2013, 4(9), 835-840. doi: 10.1021/ml4001485 PMID: 24900758
  76. Mullard, A. Antibody clamps pry open small-molecule drug discovery opportunities. Nat. Rev. Drug Discov., 2022, 21(4), 247-248. doi: 10.1038/d41573-022-00054-w PMID: 35288684
  77. Brown, A.J.H.; Bradley, S.J.; Marshall, F.H.; Brown, G.A.; Bennett, K.A.; Brown, J.; Cansfield, J.E.; Cross, D.M.; de Graaf, C.; Hudson, B.D.; Dwomoh, L.; Dias, J.M.; Errey, J.C.; Hurrell, E.; Liptrot, J.; Mattedi, G.; Molloy, C.; Nathan, P.J.; Okrasa, K.; Osborne, G.; Patel, J.C.; Pickworth, M.; Robertson, N.; Shahabi, S.; Bundgaard, C.; Phillips, K.; Broad, L.M.; Goonawardena, A.V.; Morairty, S.R.; Browning, M.; Perini, F.; Dawson, G.R.; Deakin, J.F.W.; Smith, R.T.; Sexton, P.M.; Warneck, J.; Vinson, M.; Tasker, T.; Tehan, B.G.; Teobald, B.; Christopoulos, A.; Langmead, C.J.; Jazayeri, A.; Cooke, R.M.; Rucktooa, P.; Congreve, M.S.; Weir, M.; Tobin, A.B. From structure to clinic: Design of a muscarinic M1 receptor agonist with the potential to treat Alzheimer's disease. Cell, 2021, 184(24), 5886-5901.e22. doi: 10.1016/j.cell.2021.11.001 PMID: 34822784
  78. Markert, C.; Thoma, G.; Srinivas, H.; Bollbuck, B.; Lüönd, R.M.; Miltz, W.; Wälchli, R.; Wolf, R.; Hinrichs, J.; Bergsdorf, C.; Azzaoui, K.; Penno, C.A.; Klein, K.; Wack, N.; Jäger, P.; Hasler, F.; Beerli, C.; Loetscher, P.; Dawson, J.; Wieczorek, G.; Numao, S.; Littlewood-Evans, A.; Röhn, T.A. Discovery of LYS006, a potent and highly selective inhibitor of leukotriene A4 hydrolase. J. Med. Chem., 2021, 64(4), 1889-1903. doi: 10.1021/acs.jmedchem.0c01955 PMID: 33592148
  79. Lee, K.L.; Ambler, C.M.; Anderson, D.R.; Boscoe, B.P.; Bree, A.G.; Brodfuehrer, J.I.; Chang, J.S.; Choi, C.; Chung, S.; Curran, K.J.; Day, J.E.; Dehnhardt, C.M.; Dower, K.; Drozda, S.E.; Frisbie, R.K.; Gavrin, L.K.; Goldberg, J.A.; Han, S.; Hegen, M.; Hepworth, D.; Hope, H.R.; Kamtekar, S.; Kilty, I.C.; Lee, A.; Lin, L.L.; Lovering, F.E.; Lowe, M.D.; Mathias, J.P.; Morgan, H.M.; Murphy, E.A.; Papaioannou, N.; Patny, A.; Pierce, B.S.; Rao, V.R.; Saiah, E.; Samardjiev, I.J.; Samas, B.M.; Shen, M.W.H.; Shin, J.H.; Soutter, H.H.; Strohbach, J.W.; Symanowicz, P.T.; Thomason, J.R.; Trzupek, J.D.; Vargas, R.; Vincent, F.; Yan, J.; Zapf, C.W.; Wright, S.W. Discovery of Clinical Candidate 1-(2 S, 3 S, 4 S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-ylmethoxy-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a potent, selective inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4), by fragment-based drug design. J. Med. Chem., 2017, 60(13), 5521-5542. doi: 10.1021/acs.jmedchem.7b00231 PMID: 28498658
  80. Messick, T.E.; Smith, G.R.; Soldan, S.S.; McDonnell, M.E.; Deakyne, J.S.; Malecka, K.A.; Tolvinski, L.; van den Heuvel, A.P.J.; Gu, B.W.; Cassel, J.A.; Tran, D.H.; Wassermann, B.R.; Zhang, Y.; Velvadapu, V.; Zartler, E.R.; Busson, P.; Reitz, A.B.; Lieberman, P.M. Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth. Sci. Transl. Med., 2019, 11(482), eaau5612. doi: 10.1126/scitranslmed.aau5612 PMID: 30842315
  81. Maragno, A.L.; Mistry, P.; Kotschy, A. Abstract 4482: S64315 (MIK665) is a potent and selective Mcl1 inhibitor with strong antitumor activity across a diverse range of hematologic tumor models. In: Exper. Mol. Therap; American Association for Cancer Research, 2019. doi: 10.1158/1538-7445.AM2019-4482
  82. Reich, S.H.; Sprengeler, P.A.; Chiang, G.G.; Appleman, J.R.; Chen, J.; Clarine, J.; Eam, B.; Ernst, J.T.; Han, Q.; Goel, V.K.; Han, E.Z.R.; Huang, V.; Hung, I.N.J.; Jemison, A.; Jessen, K.A.; Molter, J.; Murphy, D.; Neal, M.; Parker, G.S.; Shaghafi, M.; Sperry, S.; Staunton, J.; Stumpf, C.R.; Thompson, P.A.; Tran, C.; Webber, S.E.; Wegerski, C.J.; Zheng, H.; Webster, K.R. Structure-based design of pyridone–aminal eFT508 targeting dysregulated translation by selective mitogen-activated protein kinase interacting kinases 1 and 2(MNK1/2) inhibition. J. Med. Chem., 2018, 61(8), 3516-3540. doi: 10.1021/acs.jmedchem.7b01795 PMID: 29526098
  83. Tron, A.E.; Belmonte, M.A.; Adam, A.; Aquila, B.M.; Boise, L.H.; Chiarparin, E.; Cidado, J.; Embrey, K.J.; Gangl, E.; Gibbons, F.D.; Gregory, G.P.; Hargreaves, D.; Hendricks, J.A.; Johannes, J.W.; Johnstone, R.W.; Kazmirski, S.L.; Kettle, J.G.; Lamb, M.L.; Matulis, S.M.; Nooka, A.K.; Packer, M.J.; Peng, B.; Rawlins, P.B.; Robbins, D.W.; Schuller, A.G.; Su, N.; Yang, W.; Ye, Q.; Zheng, X.; Secrist, J.P.; Clark, E.A.; Wilson, D.M.; Fawell, S.E.; Hird, A.W. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat. Commun., 2018, 9(1), 5341. doi: 10.1038/s41467-018-07551-w PMID: 30559424
  84. Johnson, C.N.; Ahn, J.S.; Buck, I.M.; Chiarparin, E.; Day, J.E.H.; Hopkins, A.; Howard, S.; Lewis, E.J.; Martins, V.; Millemaggi, A.; Munck, J.M.; Page, L.W.; Peakman, T.; Reader, M.; Rich, S.J.; Saxty, G.; Smyth, T.; Thompson, N.T.; Ward, G.A.; Williams, P.A.; Wilsher, N.E.; Chessari, G. A fragment-derived clinical candidate for antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-(4-Fluorophenyl)methyl-5-(hydroxymethyl)-3,3-dimethyl-1 H, 2 H, 3 H -pyrrolo3,2- bpyridin-1-yl)-2-(2 R, 5 R)-5-methyl-2-((3R)-3-methylmorpholin-4-ylmethyl)piperazin-1-ylethan-1-one (ASTX660). J. Med. Chem., 2018, 61(16), 7314-7329. doi: 10.1021/acs.jmedchem.8b00900 PMID: 30091600
  85. Munck, J.M.; Berdini, V.; Bevan, L.; Brothwood, J.L.; Castro, J.; Courtin, A.; East, C.; Ferraldeschi, R.; Heightman, T.D.; Hindley, C.J.; Kucia-Tran, J.; Lyons, J.F.; Martins, V.; Muench, S.; Murray, C.W.; Norton, D.; O'Reilly, M.; Reader, M.; Rees, D.C.; Rich, S.J.; Richardson, C.J.; Shah, A.D.; Stanczuk, L.; Thompson, N.T.; Wilsher, N.E.; Woolford, A.J.A.; Wallis, N.G. ASTX029, a novel dual-mechanism ERK inhibitor, modulates both the phosphorylation and catalytic activity of ERK. Mol. Cancer Ther., 2021, 20(10), 1757-1768. doi: 10.1158/1535-7163.MCT-20-0909 PMID: 34330842
  86. Smith, C.R.; Aranda, R.; Bobinski, T.P.; Briere, D.M.; Burns, A.C.; Christensen, J.G.; Clarine, J.; Engstrom, L.D.; Gunn, R.J.; Ivetac, A.; Jean-Baptiste, R.; Ketcham, J.M.; Kobayashi, M.; Kuehler, J.; Kulyk, S.; Lawson, J.D.; Moya, K.; Olson, P.; Rahbaek, L.; Thomas, N.C.; Wang, X.; Waters, L.M.; Marx, M.A. Fragment-based discovery of MRTX1719, a synthetic lethal inhibitor of the PRMT5•MTA complex for the treatment of MTAP-deleted cancers. J. Med. Chem., 2022, 65(3), 1749-1766. doi: 10.1021/acs.jmedchem.1c01900 PMID: 35041419
  87. Konteatis, Z.; Travins, J.; Gross, S.; Marjon, K.; Barnett, A.; Mandley, E.; Nicolay, B.; Nagaraja, R.; Chen, Y.; Sun, Y.; Liu, Z.; Yu, J.; Ye, Z.; Jiang, F.; Wei, W.; Fang, C.; Gao, Y.; Kalev, P.; Hyer, M.L.; DeLaBarre, B.; Jin, L.; Padyana, A.K.; Dang, L.; Murtie, J.; Biller, S.A.; Sui, Z.; Marks, K.M. Discovery of AG-270, a first-in-class oral MAT2A inhibitor for the treatment of tumors with homozygous MTAP deletion. J. Med. Chem., 2021, 64(8), 4430-4449. doi: 10.1021/acs.jmedchem.0c01895 PMID: 33829783

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