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|Ref Type||Journal Article|
|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)|
|Date||2015 Jul 20|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Pz-1||RET Inhibitor 48 Trk Receptor Inhibitor (Pan) 30 VEGFR2 Inhibitor 36||Pz-1 is a small molecule inhibitor with activity against Ret and Kdr (VEGFR2), as well as NTRK1/2/3, which may result in tumor growth inhibition (PMID: 26126987, PMID: 34373541).|
|Gene||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 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|
|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|
|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|
|RET M918T||Advanced Solid Tumor||sensitive||Pz-1||Preclinical||Actionable||In a preclinical study, Pz-1 inhibited Ret phosphorylation in transformed cells expressing RET M918T (PMID: 26126987).||26126987|