| Autor: |
Xingyue He, Mark G. Qian, Matthew O. Duffey, Larry Cohen, Michael D. Sintchak, Mi-Sook Kim, Jessica Riceberg, Vaishali Shindi, Kelly Connolly, Jianping Guo, Agatha Zawadzka, Rachel E. Gershman, Teresa A. Soucy, Neil Bence, Zhigen Hu, Xiaofeng Yang, Shumet A. Hailu, Nina Molchinova, Nanda Gulavita, Ji Zhang, Hirotake Mizutani, Keli Song, A D Patil, Scott Freeze, Jessica Grieves, Dylan Bradley England, Roushan Afroze, James J. Minissale, Anya Lublinsky, Mitsuhiro Ito, David Lok, Scott Weston Lane, William D. Mallender, Stephen Grossman, Kara Hoar, Nitya Durvasula, Bei-Ching Chuang, Yongbo Hu, Steven P. Langston, Sai M. Pulukuri, Miho Mizutani, Ryan Chau, Nancy Bump, Katherine M. Galvin, Christopher F. Claiborne, Paul D. Greenspan, He Xu, Gaulin Jeffrey L, Melissa Gallery, Douglas Bowman, Yana Wang, Koji Ono, Mcintyre Charles |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Journal of medicinal chemistry. 64(5) |
| ISSN: |
1520-4804 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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