Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer biology & therapy	17	2	2016	199-207	Cancer Biol Ther

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 25 FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 FGFR3 Inhibitor 19 KIT Inhibitor 57 PDGFR-beta Inhibitor 14 RET Inhibitor 52	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	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
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