Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 30, Pages 8717-8721Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201501104
Keywords
inhibitors; kinases; medicinal chemistry; polypharmacology
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- MERIT grant
- MIUR (Italy)
- National Institutes of Health [T32 GM008804]
- University of Arizona
- Caldwell Health Sciences Research Fellowship
- ACS IRG grant
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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 1.0mgkg(-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 100.0mgkg(-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.
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