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	Vol	Issue	Date	Pages	Journal Short Title
Angewandte Chemie (International ed. in English)	54	30	2015 Jul 20	8717-21	Angew Chem Int Ed Engl

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
Pz-1	Pz-1	9	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Pz-1			RET Inhibitor 52 Trk Receptor Inhibitor (Pan) 31 VEGFR2 Inhibitor 37	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 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 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 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
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