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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, L. and Moccia, M. and Briggs, D.C. and Bharate, J.B. and Lakkaniga, N.R. and Knowles, P. and Tran, P. and Kharbanda, A. and Wang, X. and Leung, Y.-K. and Frett, B. and Santoro, M. and McDonald, Neil Q. and Carlomagno, F. and Li, H.-y. (2022) Discovery of N-trisubstituted Pyrimidine Derivatives as Type-I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose. Journal of Medicinal Chemistry 65 (2), pp. 1536-1551. ISSN 0022-2623.

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    Rearranged during transfection (RET) kinase is an attractive therapeutic target in cancers in which RET gene fusions and point mutations in the kinase domain are reported. Mutation of V804, the RET gatekeeper residue, leads to resistance to several FDA approved inhibitors. In this study, we discovered a series of N-trisubstituted pyrimidine derivatives as potent inhibitors for both wt-RET and RETV804M. Enzyme kinetics indicate that these inhibitors are ATP-competitive. The X-ray structure of a representative inhibitor in complex with RET reveals that the compound binds a unique pose that bifurcates beneath the P-loop; this is the first time that such a binding pose for a kinase inhibitor is described. Moreover, this binding pose explained the ability of N-trisubstituted pyrimidine compounds of targeting RETV804M. A structure activity relationship (SAR) was performed and compound 20 was identified as a lead one, displaying potent inhibition of RET and RETV804M with IC50 of 6.20nM and 18.68nM, respectively. Additionally, compound 20 showed potent anti-proliferative activity in CCDC6-RET driven LC-2/ad lung carcinoma cells. A wound healing assay indicated that compound 20 inhibits migration of RET mutant tumor cells. Analysis of apoptosis and RET phosphorylation indicated that such biological activities were mediated by RET inhibition. Collectively, N-trisubstituted pyrimidine derivatives could serve as scaffolds for the discovery and development of potent type-I RET and its gatekeeper mutant inhibitors for the treatment of RET driven cancers.


    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Neil Mcdonald
    Date Deposited: 10 May 2022 14:22
    Last Modified: 02 Aug 2023 18:15


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