title: EBI-907, a novel BRAF(V600E) inhibitor, has potent oral anti-tumor activity and a broad kinase selectivity profile.
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.
authors.affiliation: a Eternity Bioscience Inc , 2005 EastPark Blvd, Cranbury , USA.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: b Shanghai Hengrui Pharmaceutical Co. LTD , 279 Wenjing Rd, Minhang Hi-Tech Zone, Shanghai , China.
authors.forename: Biao
authors.initials: B
authors.lastname: Lu
authors.affiliation: a Eternity Bioscience Inc , 2005 EastPark Blvd, Cranbury , USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: a Eternity Bioscience Inc , 2005 EastPark Blvd, Cranbury , USA.
authors.forename: Ru
authors.initials: R
authors.lastname: Shen
authors.affiliation: a Eternity Bioscience Inc , 2005 EastPark Blvd, Cranbury , USA.
authors.forename: Yinfa
authors.initials: Y
authors.lastname: Yan
authors.affiliation: a Eternity Bioscience Inc , 2005 EastPark Blvd, Cranbury , USA.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Yang
authors.affiliation: a Eternity Bioscience Inc , 2005 EastPark Blvd, Cranbury , USA.
authors.forename: Minsheng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: b Shanghai Hengrui Pharmaceutical Co. LTD , 279 Wenjing Rd, Minhang Hi-Tech Zone, Shanghai , China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: b Shanghai Hengrui Pharmaceutical Co. LTD , 279 Wenjing Rd, Minhang Hi-Tech Zone, Shanghai , China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Cao
authors.affiliation: b Shanghai Hengrui Pharmaceutical Co. LTD , 279 Wenjing Rd, Minhang Hi-Tech Zone, Shanghai , China.
authors.forename: Hu
authors.initials: H
authors.lastname: Cao
authors.affiliation: b Shanghai Hengrui Pharmaceutical Co. LTD , 279 Wenjing Rd, Minhang Hi-Tech Zone, Shanghai , China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Fu
authors.affiliation: b Shanghai Hengrui Pharmaceutical Co. LTD , 279 Wenjing Rd, Minhang Hi-Tech Zone, Shanghai , China.
authors.forename: Aishen
authors.initials: A
authors.lastname: Gong
authors.affiliation: b Shanghai Hengrui Pharmaceutical Co. LTD , 279 Wenjing Rd, Minhang Hi-Tech Zone, Shanghai , China.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Sun
authors.affiliation: b Shanghai Hengrui Pharmaceutical Co. LTD , 279 Wenjing Rd, Minhang Hi-Tech Zone, Shanghai , China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.affiliation: c National Engineering and Research Center for Targeted Drugs, Jiangsu Hengrui Medicine Co., LTD , 7 Kunlun Shan Road, Lianyungang Economic and Technology Development Zone, Jiangsu , China.
authors.forename: Lianshan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: b Shanghai Hengrui Pharmaceutical Co. LTD , 279 Wenjing Rd, Minhang Hi-Tech Zone, Shanghai , China.
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.affiliation: a Eternity Bioscience Inc , 2005 EastPark Blvd, Cranbury , USA.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Cao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D007546:Isoquinolines / Q000008:administration & dosage*; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: C000611488:EBI-907; D007211:Indoles; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000077484:Vemurafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; BRAFV600E; EBI-907; MAPK; RAF; inhibitors; kinase
references.citation: Nature. 2010 Mar 18;464(7287):427-30
references.pmid: 20179705
references.citation: Nature. 2010 Mar 18;464(7287):431-5
references.pmid: 20130576
references.citation: Mol Cancer Ther. 2011 Mar;10(3):385-94
references.pmid: 21388974
references.citation: Cancer Res. 2011 Aug 1;71(15):5067-74
references.pmid: 21803746
references.citation: Cancer Res. 2012 Feb 15;72(4):969-78
references.pmid: 22205714
references.citation: Nature. 2012 Mar 1;483(7387):100-3
references.pmid: 22281684
references.citation: N Engl J Med. 2012 May 24;366(21):2038-40
references.pmid: 22621641
references.citation: Cancer Discov. 2012 Mar;2(3):227-35
references.pmid: 22448344
references.citation: N Engl J Med. 2012 Nov;367(18):1694-703
references.pmid: 23020132
references.citation: Nat Rev Drug Discov. 2012 Nov;11(11):873-86
references.pmid: 23060265
references.citation: Cancer Cell. 2013 May 13;23(5):594-602
references.pmid: 23680146
references.citation: Pigment Cell Melanoma Res. 2013 Sep;26(5):611-5
references.pmid: 23795808
references.citation: Nat Med. 2013 Nov;19(11):1401-9
references.pmid: 24202393
references.citation: Cancer Discov. 2014 Jan;4(1):80-93
references.pmid: 24265155
references.citation: Nature. 2002 Jun 27;417(6892):949-54
references.pmid: 12068308
references.citation: Nat Rev Cancer. 2003 Jan;3(1):11-22
references.pmid: 12509763
references.citation: Cell. 2004 Mar 19;116(6):855-67
references.pmid: 15035987
references.citation: Mol Cell. 2005 Dec 22;20(6):963-9
references.pmid: 16364920
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
references.pmid: 17126425
references.citation: Cell. 2010 Jan 22;140(2):209-21
references.pmid: 20141835
references.citation: Nature. 2010 Dec 16;468(7326):973-7
references.pmid: 21107323