CN
- 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.
Journal of medicinal chemistry (2020-10-30)
Michael J Soth, Kang Le, Maria Emilia Di Francesco, Matthew M Hamilton, Gang Liu, Jason P Burke, Chris L Carroll, Jeffrey J Kovacs, Jennifer P Bardenhagen, Christopher A Bristow, Mario Cardozo, Barbara Czako, Elisa de Stanchina, Ningping Feng, Jill R Garvey, Jason P Gay, Mary K Geck Do, Jennifer Greer, Michelle Han, Angela Harris, Zachary Herrera, Sha Huang, Virginia Giuliani, Yongying Jiang, Sarah B Johnson, Troy A Johnson, Zhijun Kang, Paul G Leonard, Zhen Liu, Timothy McAfoos, Meredith 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
PMID33118821
摘要
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.