Lu Biao, Cao Hu, Cao Jingsong, Huang Song, Hu Qiyue, Liu Dong, Shen Ru, Shen Xiaodong, Tao Weikang, Wan Hong, Wang Dan, Yan Yinfa, Yang Liuqing, Zhang Jiayin, Zhang Lei, Zhang Lianshan, Zhang Minsheng
Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
Eternity Bioscience Inc., 2005 EastPark Blvd, Cranbury, NJ 08512, USA.
Bioorg Med Chem Lett. 2016 Feb 1;26(3):819-823. doi: 10.1016/j.bmcl.2015.12.086. Epub 2015 Dec 24.
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.
基于文献报道的先导化合物PLX4720，通过骨架跃迁发现了一系列新型的吡唑并[3,4-c]异喹啉衍生物作为B-Raf(V600E)抑制剂。进一步的构效关系研究和优化导致发现了在大鼠和犬中具有良好口服生物利用度的强效B-Raf(V600E)抑制剂。其中一种化合物EBI-907（13g）在小鼠的B-Raf(V600E)依赖性Colo-205肿瘤异种移植模型中显示出优异的体内疗效，并且正在进行治疗黑色素瘤和B-Raf(V600E)相关癌症的临床前研究。
