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

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journal contribution
posted on 26.02.2021, 02:29 by Steven P. Langston, Stephen Grossman, Dylan England, Roushan Afroze, Neil Bence, Douglas Bowman, Nancy Bump, Ryan Chau, Bei-Ching Chuang, Christopher Claiborne, Larry Cohen, Kelly Connolly, Matthew Duffey, Nitya Durvasula, Scott Freeze, Melissa Gallery, Katherine Galvin, Jeffrey Gaulin, Rachel Gershman, Paul Greenspan, Jessica Grieves, Jianping Guo, Nanda Gulavita, Shumet Hailu, Xingyue He, Kara Hoar, Yongbo Hu, Zhigen Hu, Mitsuhiro Ito, Mi-Sook Kim, Scott Weston Lane, David Lok, Anya Lublinsky, William Mallender, Charles McIntyre, James Minissale, Hirotake Mizutani, Miho Mizutani, Nina Molchinova, Koji Ono, Ashok Patil, Mark Qian, Jessica Riceberg, Vaishali Shindi, Michael D. Sintchak, Keli Song, Teresa Soucy, Yana Wang, He Xu, Xiaofeng Yang, Agatha Zawadzka, Ji Zhang, Sai M. Pulukuri
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.