title: Discovery of EBI-907: A highly potent and orally active B-Raf(V600E) inhibitor for the treatment of melanoma and associated cancers.
abstract: A novel series of pyrazolo[3,4-c]isoquinoline derivatives was discovered as B-Raf(V600E) inhibitors through scaffold hopping based on a literature lead PLX4720. Further SAR exploration and optimization led to the discovery of potent B-Raf(V600E) inhibitors with good oral bioavailability in rats and dogs. One of the compounds EBI-907 (13g) demonstrated excellent in vivo efficacy in B-Raf(V600E) dependent Colo-205 tumor xenograft models in mouse and is under preclinical studies for the treatment of melanoma and B-Raf(V600E) associated cancers.
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Lu
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Cao
authors.affiliation: Eternity Bioscience Inc., 2005 EastPark Blvd, Cranbury, NJ 08512, USA.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Cao
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
authors.forename: Song
authors.initials: S
authors.lastname: Huang
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Eternity Bioscience Inc., 2005 EastPark Blvd, Cranbury, NJ 08512, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Eternity Bioscience Inc., 2005 EastPark Blvd, Cranbury, NJ 08512, USA.
authors.forename: Ru
authors.initials: R
authors.lastname: Shen
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Shen
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Eternity Bioscience Inc., 2005 EastPark Blvd, Cranbury, NJ 08512, USA.
authors.forename: Yinfa
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Eternity Bioscience Inc., 2005 EastPark Blvd, Cranbury, NJ 08512, USA.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Yang
authors.affiliation: Eternity Bioscience Inc., 2005 EastPark Blvd, Cranbury, NJ 08512, USA.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: National Engineering and Research Center for Targeted Drugs, Jiangsu Hengrui Medicine Co., Ltd, 7 Kunlun Shan Road, Lianyungang Economic and Technology Development Zone, Jiangsu Province, China.
authors.forename: Lianshan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Eternity Bioscience Inc., 2005 EastPark Blvd, Cranbury, NJ 08512, USA.
authors.forename: Minsheng
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C000611488:EBI-907; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048493:Proto-Oncogene Proteins B-raf; C039109:isoquinoline
keywords: B-Raf(V600E); Cancer; Kinase; Pyrazolo[3,4-c]isoquinoline; Scaffold hopping