An activating somatic mutation in BRAF kinase (V600E) is found in approximately 70% of melanomas, 50% of papillary thyroid cancers and 10% of colon cancers, fueling interest in BRAF (V600E) as a therapeutic target for cancer treatment. We have previously described a novel class of RAF inhibitors with initial pre-clinical profiling. This compound class has been optimized for solubility, eADME properties, and oral bioavailability. ARQ 736 has been selected as a candidate to advance into clinical testing. ARQ 736 is a potent RAF inhibitor (IC50 values of 2.6, 2.7, and 7.3 nM against BRAF, BRAF (V600E) and c-Raf-1, respectively) and extremely selective biochemically, with only 11 of 272 human kinases being inhibited within 100-fold of the IC50 against BRAF. Worthy of note, ARQ 736 was also found to be inactive against vascular endothelial growth factor receptor 2 (VEGFR2 or KDR). Despite being a pan-RAF inhibitor, at the cellular level, ARQ 736 showed a high degree of selectivity against cancer cells harboring at least one allele of BRAF (V600E) (IC50 values in cytotoxicity assays of 200-300 nM), while sparing normal cells with wild-type (wt) BRAF and wt ras as well as cancer cells harboring k-ras mutations (IC50 values in cytotoxicity assays ranging from 4 μM to greater than 10 μM). In cellular pharmacodynamic assays, ARQ 736 inhibited the MAPK pathway potently in a rapid and durable fashion (78, 65, and 11 nM respectively for inhibition of ERK phosphorylation in the human melanoma lines A375, SK-MEL-28, and Colo-205). Acute pharmacodynamic studies in vivo showed a nearly complete reduction of phospho-MEK and phospho-ERK in A375 human melanoma tumors grown in athymic xenograft models and significant tumor growth inhibition was shown in the same model with daily dosing of ARQ 736. ARQ 736 was found to be well-tolerated and orally bioavailable in dogs, and has been advanced into full pre-clinical toxicology studies, data from which will be discussed. In summary, ARQ 736 is the advanced candidate of a novel class of BRAF kinase inhibitors with excellent drug-like properties that may have clinical utility for human cancers driven by oncogenic BRAF (V600E).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4501.