TY - JOUR
T1 - Bioisosteric discovery of npa101.3, a second-generation ret/vegfr2 inhibitor optimized for single-agent polypharmacology
AU - Moccia, Marialuisa
AU - Frett, Brendan
AU - Zhang, Lingtian
AU - Lakkaniga, Naga Rajiv
AU - Briggs, David C.
AU - Chauhan, Rakhee
AU - Brescia, Annalisa
AU - Federico, Giorgia
AU - Yan, Wei
AU - Santoro, Massimo
AU - Mcdonald, Neil Q.
AU - Li, Hong Yu
AU - Carlomagno, Francesca
N1 - Funding Information:
This study was supported by NIH Grant 1R01CA197178-01A1R (to H.L.). In addition, H.L. was supported by NIH Grant 1R01CA194094-010 and University of Arkansas for Medical Sciences (UAMS) start-up funding. F.C. was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC). N.Q.M. was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001115), the UK Medical Research Council (FC001115), and the Wellcome Trust (FC001115). R.C. was supported by a grant to NQM from the Association for Multiple Endocrine Neoplasia Disorders MTC Research Fund. This work was also supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant P20 GM109005, by the UAMS Seeds of Science cancer research grant, by a grant from the American Thyroid Association (ATA/Thyca), and by the POR Campania FESR 2014–2020 “SATIN” grant.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/5/14
Y1 - 2020/5/14
N2 - 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 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 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.
AB - 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 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 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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U2 - 10.1021/acs.jmedchem.9b01336
DO - 10.1021/acs.jmedchem.9b01336
M3 - Article
C2 - 32298114
AN - SCOPUS:85084693935
SN - 0022-2623
VL - 63
SP - 4506
EP - 4516
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -