Lu Biao, Huang Song, Cao Jingsong, Hu Qiyue, Shen Ru, Wan Hong, Wang Dan, Yuan Jijun, Zhang Lei, Zhang Jiayin, Zhang Minsheng, Tao Weikang, Zhang Lianshan
Shanghai Hengrui Pharmaceutical Co. Ltd., 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
Shanghai Hengrui Pharmaceutical Co. Ltd., 279 Wenjing Rd, Minhang Hi-tech Zone, Shanghai 200245, China.
Bioorg Med Chem. 2018 Feb 1;26(3):581-589. doi: 10.1016/j.bmc.2017.12.019. Epub 2017 Dec 20.
A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231.
基于已知临床化合物，通过骨架跃迁开发了一系列新型苯并二氢呋喃衍生物作为有效的MEK抑制剂。进一步的构效关系探索和优化产生了另一个在大鼠中具有良好口服生物利用度的苯并呋喃系列。其中一种化合物EBI-1051（28d）在小鼠的colo-205肿瘤异种移植模型中显示出优异的体内疗效，适用于治疗黑色素瘤和MEK相关癌症的临床前开发研究。与AZD6244相比，EBI-1051在某些癌细胞系如colon-205、A549和MDA-MB-231中表现出更强的效力。
