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

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

  • J Med Chem. 2022 Jan 27;65(2):1536-1551. doi: 10.1021/acs.jmedchem.1c01280.
Lingtian Zhang 1,  Marialuisa Moccia 2,  David C Briggs 3,  Jaideep B Bharate 1,  Naga Rajiv Lakkaniga 4,  Phillip Knowles 3,  Wei Yan 1,  Phuc Tran 1,  Anupreet Kharbanda 1,  Xiuqi Wang 1,  Yuet-Kin Leung 5,  Brendan Frett 1,  Massimo Santoro 2,  Neil Q McDonald 3 6,  Francesca Carlomagno 2 7,  Hong-Yu Li 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
  • 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italia.
  • 3 Signalling and Structural Biology Laboratory, The Francis Crick Institute, London NW1 1AT, U.K.
  • 4 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United States.
  • 5 Department of Pharmacology & Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
  • 6 Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck College, London WC1E 7HX, U.K.
  • 7 Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, 80131 Napoli, Italia.
PMID: 35081714 DOI: 10.1021/acs.jmedchem.1c01280
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.

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