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.
MeSH terms
-
Administration, Oral
-
Animals
-
Cell Line, Tumor
-
Dogs
-
Drug Evaluation, Preclinical
-
Enzyme Inhibitors / chemistry*
-
Enzyme Inhibitors / metabolism
-
Enzyme Inhibitors / pharmacokinetics
-
Glutaminase / antagonists & inhibitors*
-
Glutaminase / genetics
-
Glutaminase / metabolism
-
Half-Life
-
Hepatocytes / cytology
-
Hepatocytes / drug effects
-
Hepatocytes / metabolism
-
Humans
-
Inhibitory Concentration 50
-
Male
-
Mice
-
Microsomes / metabolism
-
Protein Binding
-
Rats
-
Rats, Sprague-Dawley
-
Recombinant Proteins / biosynthesis
-
Recombinant Proteins / chemistry
-
Recombinant Proteins / isolation & purification
-
Structure-Activity Relationship
-
Triazoles / chemistry
-
Triazoles / metabolism
-
Triazoles / pharmacokinetics*
Substances
-
Enzyme Inhibitors
-
Recombinant Proteins
-
Triazoles
-
Glutaminase