Abstract 342: BGB-283, a slow-off inhibitor of RAF dimers, differentiates from vemurafenib in MAPK signaling inhibition

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Abstract Dysregulations of the mitogen-activated protein kinase (MAPK) signaling through abnormal expression or activating mutations of key signaling molecules, including RAS and RAF, have been identified in a wide range of cancers. Targeting these signaling molecules in the pathway represents a promising strategy to target dysregulated MAPK signaling. BGB-283 is a novel pan-RAF inhibitor and currently under clinical development to treat BRAF and KRAS/NRAS mutated tumors. In this study, we show that BGB-283 inhibits WT B-RAF dimer much more potently than vemurafenib at millimolar ATP concentration that is representative of the cellular ATP level, although BGB-283 and vemurafenib display similar inhibitory activity at the Km ATP concentration. BGB-283 has very slow off-rate and the dissociation half-life (t1/2) on WT B-RAF enzyme is well above 24 hrs. In comparison, vemurafenib has much faster off rates with t1/2 in the range of minutes. The crystal structure of BGB-283/B-RAF protein complex shows the benzimidazole and trifluoro group of BGB-283 binds significantly deeper into pocket formed by α-C helix and activation loop than vemurafenib. BGB-283 exhibits time-dependent inhibition both in biochemical assay and in B-RAF or K-RAS mutated cells. BGB-283 potently inhibits the p-ERK signaling in splicing isoform p61B-RAF(V600E) cells which were reported to be resistant to vemurafenib through a dimer mechanism. In vivo, BGB-283 significantly suppressed the tumor growth in A375-p61B-RAF(V600E) melanoma xenograft model. In addition, BGB-283 inhibits vemurafenib induced p-ERK activation and selumetinib induced p-MEK feedback activation in K-RAS mutated cancer cells. In both cases, activation is reported to be mediated by RAF dimers. Taken together, we propose that BGB-283 is a novel, slow-off RAF dimer inhibitor that targets the MAPK signaling differently from the first generation BRAF inhibitor vemurafenib. This feature of BGB-283 may help to address the drug resistance issues in BRAF mutated tumors and further expand its utility as mono- or combination therapy into RAS mutated patient populations. Citation Format: Ye Liu, Xi Yuan, Zhiyu Tang, Lai Wang, Lusong Luo, Min Wei. BGB-283, a slow-off inhibitor of RAF dimers, differentiates from vemurafenib in MAPK signaling inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 342.