title: Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology.
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.
authors.affiliation: Medicinal Chemistry Division, Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, AZ 85721 (USA).|Synactix Pharmaceuticals, Inc. 6510 N. Camino Arturo, Tucson, AZ 85718 (USA).
authors.forename: Brendan
authors.initials: B
authors.lastname: Frett
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II"/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, 80131 Naples (Italy).
authors.forename: Francesca
authors.initials: F
authors.lastname: Carlomagno
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II"/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, 80131 Naples (Italy).
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Moccia
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II"/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, 80131 Naples (Italy).
authors.forename: Annalisa
authors.initials: A
authors.lastname: Brescia
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II"/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, 80131 Naples (Italy).
authors.forename: Giorgia
authors.initials: G
authors.lastname: Federico
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II"/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, 80131 Naples (Italy).
authors.forename: Valentina
authors.initials: V
authors.lastname: De Falco
authors.affiliation: Pharmaceutical Sciences, College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, AZ 85721 (USA).
authors.forename: Brittany
authors.initials: B
authors.lastname: Admire
authors.affiliation: Medicinal Chemistry Division, Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, AZ 85721 (USA).|Chongqing University of Arts and Sciences, Chongqing, 402160 (China).
authors.forename: Zhongzhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: The University of Tennessee, Health Science Center, Memphis, TN 38163 (USA).
authors.forename: Wenqing
authors.initials: W
authors.lastname: Qi
authors.affiliation: 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.
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.affiliation: 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.|Synactix Pharmaceuticals, Inc. 6510 N. Camino Arturo, Tucson, AZ 85718 (USA). hongyuli@pharmacy.arizona.edu, contact@synactixpharma.com.
authors.forename: Hong-yu
authors.initials: HY
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015195:Drug Design; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D064798:Polypharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: inhibitors; kinases; medicinal chemistry; polypharmacology