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    Bioisosteric discovery of NPA101.3, a second generation RET/VEGFR2 inhibitor optimized for single-agent polypharmacology

    Moccia, M. and Frett, B. and Zhang, L. and Lakkaniga, R. and Briggs, D.C. and Chauhan, R. and Brescia, A. and Federico, G. and Santoro, M. and McDonald, Neil Q. and Li, H. and Carlomagno, F. (2020) Bioisosteric discovery of NPA101.3, a second generation RET/VEGFR2 inhibitor optimized for single-agent polypharmacology. Journal of Medicinal Chemistry 63 (9), pp. 4506-4516. ISSN 0022-2623.

    NPA101.3_manuscript.pdf - Author's Accepted Manuscript

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    RET receptor tyrosine kinase is a driver oncogene in human cancer. We recently identified the clinical drug candidate Pz-1, which targets RET and VEGFR2. A key in vivo metabolite of Pz-1 is its less active demethylated pyrazole analogue. Using bioisosteric substitution methods, here, we report the identification of NPA101.3, lacking the structural liability for demethylation. NPA101.3 showed selective inhibitory profile and an inhibitory concentration 50 (IC50) of <0.001 μM for both RET and VEGFR2. NPA101.3 inhibited phosphorylation of all tested RET oncoproteins as well as VEGFR2 and proliferation of cells transformed by RET. Oral administration of NPA101.3 (10 mg/kg/day) completely prevented formation of tumours induced by RET/C634Y-transformed cells, while it decreased, but did not abrogate, formation of tumours induced by a control oncogene (HRAS/G12V). The balanced synchronous inhibition of both RET and VEGFR2, as well the resistance to demethylation, renders NPA101.3 a potential clinical candidate for RET-driven cancers.


    Item Type: Article
    Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in the journal cited above, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see the DOI.
    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: 21 Apr 2020 09:22
    Last Modified: 02 Aug 2023 17:59


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