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Fragment‐Based Discovery of a Dual pan‐RET/VEGFR2 Kinase Inhibitor Optimized for Single‐Agent Polypharmacology
Author(s) -
Frett Brendan,
Carlomagno Francesca,
Moccia Maria Luisa,
Brescia Annalisa,
Federico Giorgia,
De Falco Valentina,
Admire Brittany,
Chen Zhongzhu,
Qi Wenqing,
Santoro Massimo,
Li Hongyu
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201501104
Subject(s) - tyrosine kinase inhibitor , phosphorylation , kinase , chemistry , tyrosine kinase , drug discovery , cancer research , transfection , microbiology and biotechnology , signal transduction , biochemistry , biology , cancer , gene , genetics
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.