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

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.

SUBMITTER: Zhang L 

PROVIDER: S-EPMC10536133 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Zhang Lingtian L   Moccia Marialuisa M   Briggs David C DC   Bharate Jaideep B JB   Lakkaniga Naga Rajiv NR   Knowles Phillip P   Yan Wei W   Tran Phuc P   Kharbanda Anupreet A   Wang Xiuqi X   Leung Yuet-Kin YK   Frett Brendan B   Santoro Massimo M   McDonald Neil Q NQ   Carlomagno Francesca F   Li Hong-Yu HY  

Journal of medicinal chemistry 20220101 2

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 (<i>wt</i>) RET and RET<sup>V804M</sup>, 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  ...[more]

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