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Structure of RET kinase domain bound to inhibitor JB-48
Structural highlights
Publication Abstract from PubMedMutations 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 RET(V804M), 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 RET(V804M). 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. Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose.,Zhang L, Moccia M, Briggs DC, Bharate JB, Lakkaniga NR, Knowles P, Yan W, Tran P, Kharbanda A, Wang X, Leung YK, Frett B, Santoro M, McDonald NQ, Carlomagno F, Li HY J Med Chem. 2022 Jan 27;65(2):1536-1551. doi: 10.1021/acs.jmedchem.1c01280. PMID:35081714[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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