Bioisosteric Discovery of NPA101.3, a Second-Generation RET/VEGFR2 Inhibitor Optimized for Single-Agent Polypharmacology
Open Access
- 16 April 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (9), 4506-4516
- https://doi.org/10.1021/acs.jmedchem.9b01336
Abstract
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.Keywords
Funding Information
- National Cancer Institute (1R01CA194094-010, 1R01CA197178-01A1R)
- European Commission
- Ministero dell?Istruzione, dell?Universit? e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro (IG 20793)
- University of Arkansas for Medical Sciences
- Wellcome Trust (FC001115)
- American Thyroid Association
- National Institute of General Medical Sciences (P20 GM109005)
- Regione Campania
- Cancer Research UK (FC001115)
- Association for Multiple Endocrine Neoplasia Disorders
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