SUMOylation is a reversible post translational modification that regulates protein function through covalent attachment of a SUMO (Small Ubiquitin like Modifier) protein. The SUMOylation cascade is analogous to the ubiquitination cascade and involves 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 catalytic site. Optimization of selectivity against related enzymes, as well as enhancement of mean residence time of the adduct, were critical to identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect in tumor models, culminating in the identification of the clinical molecule TAK-981.<br/>In preclinical studies with TAK-981, we have found immune cells to be particularly responsive to SUMO pathway inhibition. In vivo treatment with TAK-981 in animal models was shown to promote an antitumor immune response characterized by induction of a Type I interferon response in immune cells.  Inhibition of SUMOylation through TAK-981 may represent a novel, mechanistically unique, opportunity within the immune-oncology arena.

Discovery of TAK-981, a first-in-class inhibitor of Sumo Activating Enzyme (SAE) in phase 1 clinical trials

2019 Spring National Meeting

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