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- Title
Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology.
- Authors
Frett, Brendan; Carlomagno, Francesca; Moccia, Maria Luisa; Brescia, Annalisa; Federico, Giorgia; De Falco, Valentina; Admire, Brittany; Chen, Zhongzhu; Qi, Wenqing; Santoro, Massimo; Li, Hong-yu
- Abstract
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 type II 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, 1.0 n M of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg 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 100.0 mg 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.
- Subjects
PROTEIN-tyrosine kinase inhibitors; VASCULAR endothelial growth factor receptors; PHOSPHORYLATION; TUMOR proteins; CHEMICAL kinetics
- Publication
Angewandte Chemie, 2015, Vol 127, Issue 30, p8841
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201501104