EBI-907, a novel BRAFV600E inhibitor,has potent oral anti-tumor activity and a broad kinase selectivity profile

The oncogenic mutation of BRAF^V600E has been found in approximately 8% of all human cancers, including more than 60% of melanoma and 10% of colorectal cancers. The clinical proof of concept in treating BRAF^V600E-driving melanoma patients with the BRAF inhibitors has been well established. We have sought to identify and develop novel BRAF^V600E inhibitors with more favorable profiles. Our chemistry effort has led to the discovery of EBI-907 as a novel BRAF^V600E inhibitor with potent anti-tumor activity in vitro and in vivo. In a LanthaScreen BRAF^V600E kinase assay, EBI-907 showed an IC50 of 4.8 nM, which is >10 -fold more potent than Vemurafenib (IC50 = 58.5 nM). In addition, EBI-907 showed a broader kinase selectivity profile, with potent activity against a number of important oncogenic kinases including FGFR1-3, RET, c-Kit, and PDGFRb. Concomitant with such properties, EBI-907 exhibits potent and selective cytotoxicity against a broader range of BRAF^V600E-dependent cell lines including certain colorectal cancer cell lines with innate resistance to Vemurafenib. In BRAF^V600E-dependent human Colo-205 and A375 tumor xenograft mouse models, EBI-907 caused a marked tumor regression in a dose-dependent manner, with superior efficacy to Vemurafenib. Our results also showed that combination with EGFR or MEK inhibitor enhanced the potency of EBI-907 in cell lines with innate or acquired resistance to BRAF inhibition alone. Our findings present EBI-907 as a potent and promising BRAF inhibitor, which might be useful in broader indications.