A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment
| Autor: | John Newcomb, James M. Gavin, Nancy J. Bump, Stephen Tirrell, Lawrence R. Dick, Saurabh Menon, Jessica Huck, Petter Veiby, Benjamin S. Amidon, Yu Yang, Marc L. Hyer, Paul D. Greenspan, Fleming Paul E, Teresa A. Soucy, Jim Brownell, Michael Sintchak, Josh Powe, Steve Langston, Mark Manfredi, Judy Shi, Jeff Ciavarri, Darshan S. Sappal, Frank Bruzzese, Mike Kuranda, Katherine Galvin, Michael Milhollen, Ping Li, Neil F. Bence, Jing Tao Wu, Claudia Rabino, Chris Claiborne, Tary Traore, Jennifer Duffy, Jessica Riceberg, Robert J. Griffin, Kara Hoar, Anya Lublinsky, Bradley Stringer, Sai M Pulukuri |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex DNA Repair Ubiquitin-activating enzyme Plasma protein binding Ubiquitin-Activating Enzymes Sulfides Imides General Biochemistry Genetics and Molecular Biology Small Molecule Libraries 03 medical and health sciences Mice Ubiquitin Cell Line Tumor Neoplasms Animals Humans chemistry.chemical_classification Sulfonamides biology Chemistry Nucleosides General Medicine Small molecule Xenograft Model Antitumor Assays 030104 developmental biology Enzyme Pyrimidines Proteasome Cell culture Cancer cell Cancer research biology.protein Pyrazoles DNA Damage Protein Binding |
| Zdroj: | Nature medicine. 24(2) |
| ISSN: | 1546-170X |
| Popis: | The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment. |
| Databáze: | OpenAIRE |
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