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Angew Chem Int Ed Engl. 2015 Jul 20;54(30):8717-21. doi: 10.1002/anie.201501104. Epub 2015 Jun 30.

Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology.

Author information

1
Medicinal Chemistry Division, Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, AZ 85721 (USA).
2
Synactix Pharmaceuticals, Inc. 6510 N. Camino Arturo, Tucson, AZ 85718 (USA).
3
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II"/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, 80131 Naples (Italy).
4
Pharmaceutical Sciences, College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, AZ 85721 (USA).
5
Chongqing University of Arts and Sciences, Chongqing, 402160 (China).
6
The University of Tennessee, Health Science Center, Memphis, TN 38163 (USA).
7
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II"/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, 80131 Naples (Italy). masantor@unina.it.
8
Medicinal Chemistry Division, Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, AZ 85721 (USA). hongyuli@pharmacy.arizona.edu, contact@synactixpharma.com.
9
Synactix Pharmaceuticals, Inc. 6510 N. Camino Arturo, Tucson, AZ 85718 (USA). hongyuli@pharmacy.arizona.edu, contact@synactixpharma.com.

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 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.

KEYWORDS:

inhibitors; kinases; medicinal chemistry; polypharmacology

PMID:
26126987
PMCID:
PMC4535927
DOI:
10.1002/anie.201501104
[Indexed for MEDLINE]
Free PMC Article

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