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Ref Type Journal Article
PMID (26810733)
Authors Zhang J, Lu B, Liu D, Shen R, Yan Y, Yang L, Zhang M, Zhang L, Cao G, Cao H, Fu B, Gong A, Sun Q, Wan H, Zhang L, Tao W, Cao J
Title EBI-907, a novel BRAF(V600E) inhibitor, has potent oral anti-tumor activity and a broad kinase selectivity profile.
Journal Cancer biology & therapy
Vol 17
Issue 2
Date 2016
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
EBI-907 EBI-907 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
EBI-907 BRAF Inhibitor 20 FGFR1 Inhibitor 23 FGFR2 Inhibitor 16 FGFR3 Inhibitor 13 KIT Inhibitor 51 PDGFR-beta Inhibitor 13 RET Inhibitor 39 EBI-907 is a multi-kinase inhibitor that inhibits BRAF V600E, FGFR1-3, RET, KIT, and PDGFRb, which results in tumor growth inhibition (PMID: 26810733).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E melanoma sensitive EBI-907 Preclinical - Cell line xenograft Actionable In a preclinical study, EBI-907 inhibited BRAF and ERK signaling, resulted in growth inhibition of melanoma cells harboring BRAF V600E in culture and in cell line xenograft models (PMID: 26810733). 26810733
BRAF V600E colorectal cancer sensitive EBI-907 Preclinical - Cell line xenograft Actionable In a preclinical study, EBI-907 inhibited BRAF and ERK signaling, resulted in growth inhibition of colorectal cancer cells harboring BRAF V600E in culture and in cell line xenograft models (PMID: 26810733). 26810733