EBI-907, a novel BRAFV600E inhibitor, has potent oral anti-tumor activity and a broad kinase selectivity profile. Issue 2 (1st February 2016)

• Record Type: Journal Article
• Authors: Zhang, Jiayin; Lu, Biao; Liu, Dong; Shen, Ru; Yan, Yinfa; Yang, Liuqing; Zhang, Minsheng; Zhang, Lei; Cao, Guoqing; Cao, Hu; Fu, Beibei; Gong, Aishen; Sun, Qiming; Wan, Hong; Zhang, Lianshan; Tao, Weikang; Cao, Jingsong
• Is Part Of: Cancer biology & therapy. Volume 17:Issue 2(2016)
• Page Start: 199
• Page End: 207
• Publication Date: 2016-02-01
• Subjects: BRAF -- BRAFV600E -- EBI-907 -- inhibitors -- kinase -- MAPK -- RAF; 616.99406
• DOI: 10.1080/15384047.2016.1139231
• Languages: English
• ISSNs: 1538-4047

Abstract

Abstract: 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.