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
  • 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.
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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