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Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer.

Steven P LangstonStephen GrossmanDylan EnglandRoushan AfrozeNeil BenceDouglas BowmanNancy BumpRyan ChauBei-Ching ChuangChristopher ClaiborneLarry CohenKelly ConnollyMatthew DuffeyNitya DurvasulaScott FreezeMelissa GalleryKatherine GalvinJeffrey GaulinRachel GershmanPaul GreenspanJessica GrievesJianping GuoNanda GulavitaShumet HailuXingyue HeKara HoarYongbo HuZhigen HuMitsuhiro ItoMi-Sook KimScott Weston LaneDavid LokAnya LublinskyWilliam MallenderCharles McIntyreJames MinissaleHirotake MizutaniMiho MizutaniNina MolchinovaKoji OnoAshok PatilMark QianJessica RicebergVaishali ShindiMichael D SintchakKeli SongTeresa SoucyYana WangHe XuXiaofeng YangAgatha ZawadzkaJi ZhangSai M Pulukuri
Published in: Journal of medicinal chemistry (2021)
SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.
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