铅化合物
体内
化学
IC50型
体外
离体
药理学
药物发现
微粒体
组合化学
立体化学
生物化学
医学
生物
生物技术
作者
Jianke Ren,Yong‐Gui Gao,Wei Shi,Sheng Xu,Qinglin Wang,Damin Zhao,Lingming Kong,Wei Song,Xiaojin Wang,Ying Zhang,Xiangyi He,Yan Wang,Shunyu Tong,Peixiang Lu,Yang Li,Hongjiang Xu,Yinsheng Zhang
标识
DOI:10.1016/j.bmc.2022.117071
摘要
ALK is an attractive therapeutic target for the treatment of non-small cell lung cancer. As an emerging element in medicinal chemistry, boron has achieved great success in the discovery of antitumor drugs and antibacterial agents. Through construction of a BCC (boron-containing compound) compound library and broad kinase screening, we found the ALK inhibitor hit compound 10a. Structural optimization by CADD and isosterism revealed that lead compound 10k has improved activity (ALKL1196M IC50 = 8.4 nM, NCI-H2228 cells IC50 = 520 nM) and better in vitro metabolic stability (human liver microsomes, T1/2 = 238 min). Compound 10k showed good in vivo efficacy in a nude mouse NCI-H2228 lung cancer xenograft model with a TGI of 52 %. Molecular simulation analysis results show that the hydroxyl group on the oxaborole forms a key hydrogen bond with Asn1254 or Asp1270, and this binding site provides a new idea for drug design. This is the first publicly reported lead compound for a boron-containing ALK inhibitor.
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