1. Academic Validation
  2. 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.
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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