5. The Millenium/Takeda SUMO-activating enzyme (SAE) inhibitor TAK-981 is a mechanism-based inhibitor that covalently forms a SUMO substrate-inhibitor adduct that potently inhibits SAE, rather than reacting with SAE directly. The Takeda team has been able to successfully leverage this fascinating mechanism to develop potent inhibitors against a range of E1 enzymes including ATG7 and NEDD8-activating enzyme (NAE), one of which (pevonedistat) is currently in a Ph. III trial for AML. TAK-981 is currently in combination Ph. II trials for advanced solid tumors as an intravenous infusion. This Takeda platform is another great example of how chasing down mechanisms from a phenotypic screen can lead to a rich pipeline of new targets and clinical candidates beyond what was originally intended.