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

  • Michael J. Soth*
    Michael J. Soth
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
    *Email: [email protected]
  • Kang Le
    Kang Le
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Maria Emilia Di Francesco
    Maria Emilia Di Francesco
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Matthew M. Hamilton
    Matthew M. Hamilton
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Gang Liu
    Gang Liu
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Jason P. Burke
    Jason P. Burke
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Chris L. Carroll
    Chris L. Carroll
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Jeffrey J. Kovacs
    Jeffrey J. Kovacs
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Jennifer P. Bardenhagen
    Jennifer P. Bardenhagen
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Christopher A. Bristow
    Christopher A. Bristow
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Mario Cardozo
    Mario Cardozo
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Barbara Czako
    Barbara Czako
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Elisa de Stanchina
    Elisa de Stanchina
    Antitumor Assessment Core Facility—Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
  • Ningping Feng
    Ningping Feng
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Jill R. Garvey
    Jill R. Garvey
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Jason P. Gay
    Jason P. Gay
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Mary K. Geck Do
    Mary K. Geck Do
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Jennifer Greer
    Jennifer Greer
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Michelle Han
    Michelle Han
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Angela Harris
    Angela Harris
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Zachary Herrera
    Zachary Herrera
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Sha Huang
    Sha Huang
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Virginia Giuliani
    Virginia Giuliani
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Yongying Jiang
    Yongying Jiang
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Sarah B. Johnson
    Sarah B. Johnson
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Troy A. Johnson
    Troy A. Johnson
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Zhijun Kang
    Zhijun Kang
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Paul G. Leonard
    Paul G. Leonard
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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    Zhen Liu
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Timothy McAfoos
    Timothy McAfoos
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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    Meredith Miller
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Pietro Morlacchi
    Pietro Morlacchi
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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    Robert A. Mullinax
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Wylie S. Palmer
    Wylie S. Palmer
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Jihai Pang
    Jihai Pang
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Norma Rogers
    Norma Rogers
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Charles M. Rudin
    Charles M. Rudin
    Drunkenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York New York 10065, United States
  • Hannah E. Shepard
    Hannah E. Shepard
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Nakia D. Spencer
    Nakia D. Spencer
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Jay Theroff
    Jay Theroff
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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    Qi Wu
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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    Alan Xu
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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    Ju Anne Yau
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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  • Giulio Draetta
    Giulio Draetta
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Carlo Toniatti
    Carlo Toniatti
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • Timothy P. Heffernan
    Timothy P. Heffernan
    Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
  • , and 
  • Philip Jones
    Philip Jones
    Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
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Cite this: J. Med. Chem. 2020, 63, 21, 12957–12977
Publication Date (Web):October 29, 2020
https://doi.org/10.1021/acs.jmedchem.0c01398
Copyright © 2020 American Chemical Society

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    Abstract

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    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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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01398.

    • Molecular formula strings (CSV)

    • Experimental details for the preparation of compounds 526; UPLC and high-resolution mass spectrometry data for componds 2427; logD, logP, and pKa determinations for compound 27; experimental procedures for oral dosing formulations and additional in vivo studies; standard deviations for GLS-1 and A549 assay results for compounds 2, 4, and 527; representative IC50 curve for compound 27 in the A549 assay; and Kinomescan and CEREP off-target screening data for 27; Figures S1–S3 (PDF)

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