| Literature DB >> 29334375 |
Marc L Hyer1, Michael A Milhollen1, Jeff Ciavarri1, Paul Fleming1, Tary Traore1, Darshan Sappal1, Jessica Huck1, Judy Shi1, James Gavin1, Jim Brownell1, Yu Yang1, Bradley Stringer1, Robert Griffin1, Frank Bruzzese1, Teresa Soucy1, Jennifer Duffy1, Claudia Rabino1, Jessica Riceberg1, Kara Hoar1, Anya Lublinsky1, Saurabh Menon1, Michael Sintchak1, Nancy Bump1, Sai M Pulukuri1, Steve Langston1, Stephen Tirrell1, Mike Kuranda1, Petter Veiby1, John Newcomb1, Ping Li1, Jing Tao Wu1, Josh Powe1, Lawrence R Dick1, Paul Greenspan1, Katherine Galvin1, Mark Manfredi1, Chris Claiborne1, Benjamin S Amidon1, Neil F Bence1.
Abstract
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.Entities:
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Year: 2018 PMID： 29334375 DOI： 10.1038/nm.4474
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440