Burger, Matthew, Aversa, Robert, Taft, Benjamin, La Bonte, Laura, Cooke, Vesselina, Polyakov, Valery, Mishina, Yuji, Haling, Jake, Tellew, John, Iyer, Raman, Tian, Hung, Mathews Griner, Lesley, Mamo, Mulugeta, Huang, Shenlin, Gampa, Kalyani and Feng, Fei (2019) Design and Discovery of N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (LXH254), A selective, efficacious, well-tolerated RAF inhibitor targeting RAS mutant cancers: The path to the clinic. Journal of medicinal chemistry, 63 (5). pp. 2013-2027.

Abstract

RAS and BRAF oncogenes are mutated in more than one-third of human cancers and exquisite dependency on CRAF, MEK1/2 and ERK1/2 has been demonstrated in preclinical models of RAS mutant cancer. Direct pharmacological inhibition of RAS has remained elusive and efforts to target CRAF have been challenging due to the nature of the RAF signaling complex downstream of activated RAS and the poor overall kinase selectivity profile of putative RAF inhibitors such as sorafenib and RAF265. Herein, we describe 15 (LXH254), a selective B/C RAF inhibitor, which has been developed through a hypothesis-driven approach focusing on drug-like properties. We have previously disclosed the discovery of 3 (RAF709), a preclinical tool compound which was potent, selective, efficacious, and well-tolerated in preclinical models, but the high intrinsic clearance [HLM Cl(int) = 94] precluded further development.X The high clearance of 3 by HLM prompted the medicinal chemistry team to further investigate close analogs as well as novel scaffolds. While keeping drug-like properties in mind, the team identified multiple cell-potent scaffolds with low-to-moderate human clearance and progressed them into in-vivo pharmacology studies. Unexpectedly, the majority of novel scaffolds caused significant body weight loss in mice for unknown reasons, with the 2-pyridine series emerging as the only scaffold which was not plagued by this problem. A structure-based approach led to the realization that an alcohol side-chain in the 2-position of the pyridine could interact with the DFG loop and significantly improve cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition of CYP3A4 (TDI) led to the discovery of 15, which had favorable PK and proved to be efficacious in multiple xenograft models such as Calu-6 (KRASQ61K),with a favorable therapeutic index. Due to its excellent in vitro/ in vivo properties, it has progressed through preclinical toxicology studies and now being tested as a single agent and as a combination partner in phase 1 clinical trials

Item Type:	Article
Keywords:	RAF709, LXH254, structure based drug design, TDI, Ras mutant cells
Date Deposited:	16 Jun 2020 00:45
Last Modified:	16 Jun 2020 00:45
URI:	https://oak.novartis.com/id/eprint/37673