Discovery of N-trisubstituted pyrimidine derivatives as type I RET and RET gatekeeper mutant inhibitors with a novel kinase binding pose
Authors list
Lingtian Zhang Marialuisa Moccia David Briggs Jaideep B Bharate Naga Rajiv Lakkaniga Phillip Knowles Wei Yan Phuc Tran Anupreet Kharbanda Xiuqi Wang Yuet-Kin Leung Brendan Frett Massimo Santoro Neil McDonald Francesca Carlomagno Hongy-yu LiAbstract
Mutations of the rearranged during transfection (RET) kinase are frequently reported in cancer, which make it as an attractive therapeutic target. Herein, we discovered a series of N-trisubstituted pyrimidine derivatives as potent inhibitors for both wild-type (wt) RET and RETV804M, which is a resistant mutant for several FDA-approved inhibitors. The X-ray structure of a representative inhibitor with RET revealed that the compound binds in a unique pose that bifurcates beneath the P-loop and confirmed the compound as a type I inhibitor. Through the structure-activity relationship (SAR) study, compound 20 was identified as a lead compound, showing potent inhibition of both RET and RETV804M. Additionally, compound 20 displayed potent antiproliferative activity of CCDC6-RET-driven LC-2/ad cells. Analysis of RET phosphorylation indicated that biological activity was mediated by RET inhibition. Collectively, N-trisubstituted pyrimidine derivatives could serve as scaffolds for the discovery and development of potent inhibitors of type I RET and its gatekeeper mutant for the treatment of RET-driven cancers.
Journal details
Journal Journal of Medicinal Chemistry
Volume 65
Issue number 2
Pages 1536-1551
Available online
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Publisher website (DOI) 10.1021/acs.jmedchem.1c01280
Europe PubMed Central 35081714
Pubmed 35081714
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