Preclinical Efficacy and Safety of the Novel Antidiabetic, Antiobesity MetAP2 Inhibitor ZGN-1061

The Journal of Pharmacology and Experimental Therapeutics
Bryan F BurkeyJ E Vath

Abstract

Methionine aminopeptidase 2 (MetAP2) inhibition is a promising approach to treating diabetes, obesity, and associated metabolic disorders. Beloranib, a MetAP2 inhibitor previously investigated for treatment of Prader-Willi syndrome, was associated with venous thrombotic adverse events likely resulting from drug effects on vascular endothelial cells (ECs). Here, we report the pharmacological characterization of ZGN-1061, a novel MetAP2 inhibitor being investigated for treatment of diabetes and obesity. Four weeks of subcutaneous administration of ZGN-1061 to diet-induced obese (DIO) insulin-resistant mice produced a 25% reduction in body weight, primarily due to reduced fat mass, that was comparable to beloranib. ZGN-1061 also produced improvements in metabolic parameters, including plasma glucose and insulin, and, in HepG2 cells, initiated gene changes similar to beloranib that support observed in vivo pharmacodynamics. In vitro studies in ECs demonstrated that ZGN-1061 effects on EC proliferation and coagulation proteins were greatly attenuated, or absent, relative to beloranib, due to lower intracellular drug concentrations, shorter half-life of inhibitor-bound MetAP2 complex, and reduced cellular enzyme inhibition. In dogs, ...Continue Reading

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Citations

Jul 3, 2019·Adipocyte·Md Abu Bakkar SiddikVijay Hegde
Dec 19, 2019·Expert Opinion on Investigational Drugs·Candida J Rebello, Frank L Greenway
Jan 1, 2020·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·Qiming TanAndrea M Haqq
Jan 29, 2020·American Journal of Physiology. Endocrinology and Metabolism·Mary Courtney MooreAlan D Cherrington
Sep 14, 2019·Nature Reviews. Cancer·Sydney M SandersonJason W Locasale
Aug 12, 2020·Antimicrobial Agents and Chemotherapy·Janak PadiaOsnat Herzberg
Dec 14, 2018·CNS Drugs·Susan L McElroyFrancisco Romo-Nava
Nov 7, 2019·Orphanet Journal of Rare Diseases·Dibia Liz Pacoricona AlfaroMaithé Tauber
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Jun 30, 2021·Archiv der Pharmazie·Deepa R ParmarAnand G Vala
Aug 28, 2021·Trends in Pharmacological Sciences·Andrea Goya GrocinEdward W Tate

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