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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