Reference Detail

Ref Type Journal Article
PMID (26126987)
Authors Frett B, Carlomagno F, Moccia ML, Brescia A, Federico G, De Falco V, Admire B, Chen Z, Qi W, Santoro M, Li HY
Title Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology.
Journal Angewandte Chemie (International ed. in English)
Vol 54
Issue 30
Date 2015 Jul 20
URL
Abstract Text 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 nM 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Pz-1 RET Inhibitor 36 VEGFR2 Inhibitor 34 Pz-1 is an inhibitor with activity against Ret and Kdr, which may result in tumor growth inhibition (PMID: 26126987).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET C634R Advanced Solid Tumor sensitive Pz-1 Preclinical - Cell line xenograft Actionable In a preclinical study, Pz-1 inhibited Ret signaling in transformed cells over expressing RET C634R and inhibited tumor growth in cell line xenografts models (PMID: 26126987). 26126987
RET V804M Advanced Solid Tumor predicted - sensitive Pz-1 Preclinical Actionable In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET V804M (PMID: 26126987). 26126987
RET M918T Advanced Solid Tumor predicted - sensitive Pz-1 Preclinical Actionable In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET M918T (PMID: 26126987). 26126987
RET V804L Advanced Solid Tumor predicted - sensitive Pz-1 Preclinical Actionable In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET V804L (PMID: 26126987). 26126987
HRAS G12V Advanced Solid Tumor sensitive Pz-1 Preclinical - Cell line xenograft Actionable In a preclinical study, Pz-1 reduced tumor growth in xenograft models of transformed cells over expressing HRAS G12V in a dose-dependent manner (PMID: 26126987). 26126987
KDR wild-type Advanced Solid Tumor predicted - sensitive Pz-1 Preclinical Actionable In a preclinical study, Pz-1 inhibited Kdr2 phosphorylation in transformed cells expressing KDR wild-type (PMID: 26126987). 26126987