Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants

In order to explore novel ALK and ROS1 dual inhibitors capable of overcoming crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxic activity. In this work, we retained the 2,4-diarylaminopyrimidine scaffold and derivatize the DAAP scaffold with sulfonyl and acrylamide moieties to extend the structure–activity relationship (SAR) study. To our delight, some compounds exhibited excellent inhibitory activity with a double-digit nanomolar level in MTT assay. Four compounds were selected for enzymic assays further, the results led to the identification of a potent ALK and ROS1 dual inhibitor X-17, with IC50 values of 3.7 nM, 2.3 nM, 8.9 nM and 1.9 nM against ALK, ALKL1196M, ALKG1202R and ROS1, respectively. Ultimately, the molecular docking studies on X-17 clearly disclosed reasonable and optimal binding interactions with ALK. READ ARTICLE

Bioorganic & Medicinal Chemistry DOI:10.1016/j.bmc.2020.115719

Authors: Minglin Zhu, Wei Li, Tianming Zhao, Yuxiang Chen, Tong Li, Shangfei Wei, Ming Guo, Xin Zhai

Pre-ClinicalKirk SmithOctober 15, 20202, 4-Diarylaminopyrimidine, Dual inhibitor, ALK, ROS1, Crizotinib-resistant

Pyrroformyl-containing 2,4-diaminopyrimidine derivatives as a new optimization strategy of ALK inhibitors combating mutations

Aiming to identify new optimization strategy effective for ALK-mutations, two series of pyrroformyl-containing 2,4-diaminopyrimidine compounds (11a-o, 12a-o) were designed, synthesized and evaluated for their anti-proliferative activities against three cancer cell lines in vitro by MTT assay. The biological evaluations on cellular assay resulted in discovery of compound 11k, which performed considerable activity with IC50 value of 0.034 μM against H2228 cell. Meanwhile, 11k exhibited outstanding enzymatic inhibitory potency with IC50 values of 1.9 nM and 3.1 nM against ALKWT and ALKL1196M, respectively, surpassing the reference ceritinib (IC50 = 2.4 nM and 7.6 nM). Ultimately, the binding mode of 11k with ALK was established to explore the SARs. Overall, 11k was considered as a promising ALK inhibitor for mutation treatment. READ ARTICLE

Bioorganic & Medicinal Chemistry DOI:10.1016/j.bmc.2020.115715

Authors: Meng Cao, Yuxiang Chen, Tianming Zhao, Shangfei Wei, Ming Guo, Xin Zhai

EditorialKirk SmithOctober 1, 2020ALK inhibitor, 2, 4-Diaminopyrimidine, Pyrroformyl, L1196M mutation, Synthesis, Biological evaluations