3 years ago

A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment

A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment
Paul Greenspan, Ping Li, Petter Veiby, Teresa Soucy, Judy Shi, Jeff Ciavarri, Jessica Riceberg, Benjamin S Amidon, John Newcomb, Michael Sintchak, Robert Griffin, Mark Manfredi, Sai M Pulukuri, Darshan Sappal, Neil F Bence, Jim Brownell, Jessica Huck, Michael A Milhollen, Tary Traore, Jennifer Duffy, Kara Hoar, Marc L Hyer, Mike Kuranda, Nancy Bump, Paul Fleming, Jing Tao Wu, Yu Yang, Frank Bruzzese, Lawrence R Dick, Saurabh Menon, Stephen Tirrell, Bradley Stringer, Anya Lublinsky, Steve Langston, James Gavin, Chris Claiborne, Katherine Galvin, Josh Powe, Claudia Rabino
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.

Publisher URL: https://www.nature.com/articles/nm.4474

DOI: 10.1038/nm.4474

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