Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.
Michael J SothKang LeMaria Emilia Di FrancescoMatthew M HamiltonGang LiuJason P BurkeChris L CarrollJeffrey J KovacsJennifer P BardenhagenChristopher A BristowMario CardozoBarbara CzakoElisa de StanchinaNingping FengJill R GarveyJason P GayMary K Geck DoJennifer GreerMichelle HanAngela HarrisZachary HerreraSha HuangVirginia GiulianiYongying JiangSarah B JohnsonTroy A JohnsonZhijun KangPaul G LeonardZhen LiuTimothy McAfoosMeredith MillerPietro MorlacchiRobert A MullinaxWylie S PalmerJihai PangNorma RogersCharles M RudinHannah E ShepardNakia D SpencerJay TheroffQi WuAlan XuJu Anne YauGiulio DraettaCarlo ToniattiTimothy P HeffernanPhilip JonesPublished in: Journal of medicinal chemistry (2020)
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.