Open AccessDiscovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties
Author(s) -
Michael Soth,
Le Kang,
Maria Emilia Di Francesco,
Matthew M. Hamilton,
Gang Liu,
Jason P. Burke,
Chris L Carroll,
Jeffery Kovacs,
Jennifer Bardenhagen,
Christopher A. Bristow,
Mario Cardozo,
Barbara Czakó,
Elisa de Stanchina,
Ningping Feng,
Jill R Garvey,
Mary Geck,
Jennifer Greer,
Michelle Han,
Alexandra R. Harris,
Zachary Herrera,
Sha Huang,
Virginia Giuliani,
Yongying Jiang,
Sarah Johnson,
Troy A. Johnson,
Zhijun Kang,
Paul G. Leonard,
Zhen Liu,
Timothy McAfoos,
Meredith A. Miller,
Pietro Morlacchi,
Robert A. Mullinax,
Wylie S. Palmer,
Jihai Pang,
Norma Rogers,
Charles M. Rudin,
Hannah E. Shepard,
Nakia D. Spencer,
Jay Theroff,
Qi Wu,
Alan Xu,
Ju Anne Yau,
Giulio Draetta,
Carlo Toniatti,
Timothy P. Heffernan,
Philip Jones
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01398
Subject(s) - chemistry , glutaminase , in vivo , pharmacokinetics , pharmacology , glutamine , drug discovery , biochemistry , biology , amino acid , microbiology and biotechnology
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.