2. Academic Validation
  3. Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties

  • J Med Chem. 2020 Nov 12;63(21):12957-12977. doi: 10.1021/acs.jmedchem.0c01398.
Michael J Soth 1,  Kang Le 1,  Maria Emilia Di Francesco 1,  Matthew M Hamilton 1,  Gang Liu 1,  Jason P Burke 1,  Chris L Carroll 1,  Jeffrey J Kovacs 2,  Jennifer P Bardenhagen 1,  Christopher A Bristow 2,  Mario Cardozo 1,  Barbara Czako 1,  Elisa de Stanchina 3,  Ningping Feng 2,  Jill R Garvey 2,  Jason P Gay 2,  Mary K Geck Do 1,  Jennifer Greer 2,  Michelle Han 1,  Angela Harris 2,  Zachary Herrera 1,  Sha Huang 1,  Virginia Giuliani 2,  Yongying Jiang 1,  Sarah B Johnson 2,  Troy A Johnson 1,  Zhijun Kang 1,  Paul G Leonard 1,  Zhen Liu 1,  Timothy McAfoos 1,  Meredith Miller 2,  Pietro Morlacchi 1,  Robert A Mullinax 2,  Wylie S Palmer 1,  Jihai Pang 1,  Norma Rogers 1,  Charles M Rudin 4,  Hannah E Shepard 1,  Nakia D Spencer 2,  Jay Theroff 1,  Qi Wu 1,  Alan Xu 1,  Ju Anne Yau 1,  Giulio Draetta 1 2,  Carlo Toniatti 2,  Timothy P Heffernan 2,  Philip Jones 1
Affiliations

Affiliations

  • 1 Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 2 Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 3 Antitumor Assessment Core Facility-Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
  • 4 Drunkenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York New York 10065, United States.
PMID: 33118821 DOI: 10.1021/acs.jmedchem.0c01398
Abstract

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known Glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit Glutaminase in humans.

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