Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants.
Basic Information
ID: ALA4665877
Journal: Bioorg Med Chem
Title: Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants.
Authors: Zhu M,Li W,Zhao T,Chen Y,Li T,Wei S,Guo M,Zhai X
Abstract: 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 IC values of 3.7 nM, 2.3 nM, 8.9 nM and 1.9 nM against ALK, ALK, ALK and ROS1, respectively. Ultimately, the molecular docking studies on X-17 clearly disclosed reasonable and optimal binding interactions with ALK.
CiteXplore: 33069075
DOI: 10.1016/j.bmc.2020.115719
Patent ID: ┄