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

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.