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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

DOI: 10.1021/acs.jmedchem.1c01280 DOI Help

Authors: Lingtian Zhang (University of Arkansas for Medical Sciences) , Marialuisa Moccia (Università di Napoli) , David C. Briggs (The Francis Crick Institute) , Jaideep B. Bharate (University of Arkansas for Medical Science) , Naga Rajiv Lakkaniga (The Scripps Research Institute) , Phillip Knowles (The Francis Crick Institute) , Wei Yan (University of Arkansas for Medical Sciences) , Phuc Tran (University of Arkansas for Medical Sciences) , Anupreet Kharbanda (niversity of Arkansas for Medical Sciences) , Xiuqi Wang (University of Arkansas for Medical Sciences) , Yuet-Kin Leung (University of Arkansas for Medical Sciences) , Brendan Frett (University of Arkansas for Medical Sciences) , Massimo Santoro (Università di Napoli) , Neil Q. Mcdonald (he Francis Crick Institute; Birkbeck College, London) , Francesca Carlomagno (Università di Napoli) , Hong-Yu Li (University of Arkansas for Medical Sciences)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 65 , PAGES 1536 - 1551

State: Published (Approved)
Published: January 2022

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.

Journal Keywords: Peptides and proteins; Pyrimidine; Inhibitors; Inhibition; Fluorescence resonance energy transfer

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 09/02/2022 08:36

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)