Posts tagged ALK & ROS1 inhibitors
An exploration of solvent-front region high affinity moiety leading to novel potent ALK & ROS1 dual inhibitors with mutant-combating effects
An exploration of solvent-front region high affinity moiety leading to novel potent ALK & ROS1 dual inhibitors with mutant-combating effects

The pyrimidine-2,4-diamine analogs exerted excellent activities in down-regulation of ALK phosphorylation. However, the prevalent drug-resistant site-mutation has gradually prevented the agents from being widely used. Herein, we conducted an exploration of high affinity moiety that bound to the solvent-front region (G1202R located) within the ATP binding site of ALK leading to the synthesis of thirty-five pyrimidine-2,4-diamine derivatives. Among these compounds, urea group was extensively derivatized which finally resulted in the identification of the ‘semi-free urea’ compound 39. All compounds were assayed cytotoxicity and enzymatic activities and 39 turned out to be the most potent one with IC50 values of 2.1, 0.91, 4.3 and 0.73 nM towards ALKwt, ALKL1196M, ALKG1202R and ROS1, respectively. The performances of 39 on ALK- & ROS1-dependent cell lines were in good accordance with enzymatic activities with IC50 values below 0.06 µM. Besides, 39 induced cell apoptosis in a dose-dependent..... READ ARTICLE

Bioorganic & Medicinal Chemistry DOI:10.1016/j.bmc.2019.115051

Authors: Hongrui Lei, Fang Jia, Meng Cao, Jie Wang, Ming Guo, Minglin Zhu, Daiying Zuo, Xin Zhai

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Review PaperKirk SmithPyrimidine-2, 4-Diamine, Solvent front, ALK & ROS1 inhibitors, Mutation-combating, Apoptosis-inducing
Discovery of novel mutant-combating ALK and ROS1 dual inhibitors bearing imidazolidin-2-one moiety with reasonable PK properties
Discovery of novel mutant-combating ALK and ROS1 dual inhibitors bearing imidazolidin-2-one moiety with reasonable PK properties

Aiming to identify novel potent ALK and ROS1 dual inhibitors, the relatively bulky piperidine fragment in ceritinib was replaced with substituted imidazolidin-2-one moiety which gave rise to a series of 2,4-diaryl-aminopyrimidine (DAAP) analogs (6–33). SAR studies were conducted based on cellular assays on five cell lines and most compounds exerted moderated to excellent activities. Among them, 15 showed excellent inhibitory activities against ROS1 and ALK positive cell lines, especially Ba/F3G1202R, with IC50 values ranging from 14 to 37 nM. As a continuation, several compounds were tested in enzymatic assays and 15 displayed encouraging activities against wild-type ALK (1.2 nM), ROS1(0.43 nM) as well as extremely resistant ALKL1196M and ALKG1202R mutants with IC50 values of 0.73 nM and 6.7 nM, respectively. To our delight, both cellular and enzymatic results of 15 were in good accordance with western blot assays on H2228 and HCC78 cell lines. Importantly, pharmacokinetic (PK) profile..... READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2019.03.038

Authors: Hongrui Lei, Nan Jiang, Xiuqi Miao, Lingyun Xing, Ming Guo, Yang Liu, Haowen Xu, Ping Gong, Daiying Zuo, Xin Zhai

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Pre-ClinicalKirk SmithCeritinib analogs, Imidazolidin-2-one, ALK & ROS1 inhibitors, PK profiles, Molecular docking