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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Kulolide, a cyclic depsipeptide, was isolated from a cephalaspidean mollusk, Philinopsis speciosa Pease, 1860. Kulolide is made up of five amino acid residues, one each of L-Ala, L-Pro, and N-Me-D-Val and two of L-Val, and two carboxylic acids, L-3-phenyllactic acid and the unprecedented (R)-3-hydroxy-2,2-dimethyl-7-octynoic acid. The kulolide structure was elucidated by spectral techniques and hydrolytic reactions. Kulolide is active against L-1210 leukemia cells and P388 murine leukemia cells at IC 50 values of 0.7 and 2.1 µg/mL, respectively. Kulolide caused morphological change against rat 3Y1 fibroblast cells at the concentration of 50 µM.