Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 28, Issue 20, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115719
Keywords
2,4-Diarylaminopyrimidine; Dual inhibitor; ALK; ROS1; Crizotinib-resistant
Funding
- National Natural Science Foundation of China [81673308]
- Youth Backbone Talent Training Project of Shenyang Pharmaceutical University [ZQN2018008]
- Development Project of Ministry of Education Innovation Team [IRT1073]
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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, ALK(L1196M), ALK(G1202R) and ROS1, respectively. Ultimately, the molecular docking studies on X-17 clearly disclosed reasonable and optimal binding interactions with ALK.
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