Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose

Lingtian Zhang, Marialuisa Moccia, David C. 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 Q. McDonald, Francesca Carlomagno, Hong Yu Li

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1536-1551
Number of pages16
JournalJournal of Medicinal Chemistry
Volume65
Issue number2
DOIs
StatePublished - Jan 27 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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