ABSTRACT
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.
Subject(s)
Antineoplastic Agents/chemistry , Drug Discovery/methods , Mutation/genetics , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Animals , Antineoplastic Agents/pharmacology , Drug Design , Drug Discovery/trends , Humans , Molecular Docking Simulation/methods , Molecular Docking Simulation/trends , Mutation/drug effects , Protein Kinase Inhibitors/pharmacology , Xenograft Model Antitumor Assays/methodsABSTRACT
RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.
Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Antineoplastic Agents/pharmacology , Benzamides/pharmacology , raf Kinases/antagonists & inhibitors , ras Proteins/genetics , 2,2'-Dipyridyl/chemistry , 2,2'-Dipyridyl/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Benzamides/chemistry , Crystallography, X-Ray , Dogs , Drug Design , Drug Discovery , Drug Stability , Humans , Inhibitory Concentration 50 , Mice , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/genetics , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins p21(ras)/genetics , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The allene ether version of the Nazarov cyclization was used to construct the cyclopentane dione portion of madindolines A and B. The racemic cyclopentane dione from the Nazarov cyclization was converted to an enol ether that was combined with the chiral, nonracemic hydroxyfuroindoline in a Mannich reaction. Deprotection and oxidation led to (+)-madindoline A and (+)-madindoline B. [reaction: see text].
