期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 9, 页码 4506-4516出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01336
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资金
- NIH [1R01CA197178-01A1R, 1R01CA194094-010]
- University of Arkansas for Medical Sciences (UAMS)
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Francis Crick Institute
- Cancer Research UK [FC001115]
- UK Medical Research Council [FC001115]
- Wellcome Trust [FC001115]
- Association for Multiple Endocrine Neoplasia Disorders MTC Research Fund
- Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20 GM109005]
- UAMS Seeds of Science cancer research grant
- American Thyroid Association (ATA/Thyca)
- POR Campania FESR 2014-2020 SATIN grant
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 a selective inhibitory profile and an inhibitory concentration 50 (IC50) of <0.003 mu M 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 tumors induced by RET/C634Y-transformed cells, while it weakened, but did not abrogate, formation of tumors 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.
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