Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology

Brendan Frett, Francesca Carlomagno, Maria Luisa Moccia, Annalisa Brescia, Giorgia Federico, Valentina Defalco, Brittany Admire, Zhongzhu Chen, Wenqing Qi, Massimo Santoro, Hong Yu Li

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen led to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a typeII tyrosine kinase inhibitor that is able to bind the "DFG-out" conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown to be active on VEGFR2, which can block the blood supply required for RET-stimulated growth. In cell-based assays, 1.0nM of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0mg kg-1 day-1 per os, Pz-1 abrogated the formation of tumors induced by RET-mutant fibroblasts and blocked the phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 featured no detectable toxicity at concentrations of up to 100.0mg kg-1, which indicates a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry/polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways. Dual inhibition: A kinase-directed fragment-based screen identified a novel active pharmacophore for the RET tyrosine kinase (RET=rearranged during transfection). In a medicinal chemistry/polypharmacology approach, Pz-1 was found to be a dual pan-RET/VEGFR2 inhibitor and able to simultaneously treat the parenchyma (RET) and stroma (VEGFR2) of RET-driven tumors in cell and xenograft models.

Original languageEnglish (US)
Pages (from-to)8717-8721
Number of pages5
JournalAngewandte Chemie - International Edition
Issue number30
StatePublished - Jul 20 2015


  • inhibitors
  • kinases
  • medicinal chemistry
  • polypharmacology

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)


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