Bioisosteric discovery of npa101.3, a second-generation ret/vegfr2 inhibitor optimized for single-agent polypharmacology

Marialuisa Moccia, Brendan Frett, Lingtian Zhang, Naga Rajiv Lakkaniga, David C. Briggs, Rakhee Chauhan, Annalisa Brescia, Giorgia Federico, Wei Yan, Massimo Santoro, Neil Q. Mcdonald, Hong Yu Li, Francesca Carlomagno

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)4506-4516
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - May 14 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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