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

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

  • Angew Chem Int Ed Engl. 2015 Jul 20;54(30):8717-21. doi: 10.1002/anie.201501104.
Brendan Frett 1 2,  Francesca Carlomagno 3,  Maria Luisa Moccia 3,  Annalisa Brescia 3,  Giorgia Federico 3,  Valentina De Falco 3,  Brittany Admire 4,  Zhongzhu Chen 1 5,  Wenqing Qi 6,  Massimo Santoro 7,  Hong-yu Li 8 9
Affiliations

Affiliations

  • 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). [email protected].
  • 8 Medicinal Chemistry Division, Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, AZ 85721 (USA). [email protected], [email protected].
  • 9 Synactix Pharmaceuticals, Inc. 6510 N. Camino Arturo, Tucson, AZ 85718 (USA). [email protected], [email protected].
PMID: 26126987 DOI: 10.1002/anie.201501104
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/KDR/Flk-1, 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/KDR/Flk-1 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.

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