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

  • Nat Med. 2018 Feb;24(2):186-193. doi: 10.1038/nm.4474.
Marc L Hyer  1 ,  Michael A Milhollen  1 ,  Jeff Ciavarri  1 ,  Paul Fleming  1 ,  Tary Traore  1 ,  Darshan Sappal  1 ,  Jessica Huck  1 ,  Judy Shi  1 ,  James Gavin  1 ,  Jim Brownell  1 ,  Yu Yang  1 ,  Bradley Stringer  1 ,  Robert Griffin  1 ,  Frank Bruzzese  1 ,  Teresa Soucy  1 ,  Jennifer Duffy  1 ,  Claudia Rabino  1 ,  Jessica Riceberg  1 ,  Kara Hoar  1 ,  Anya Lublinsky  1 ,  Saurabh Menon  1 ,  Michael Sintchak  1 ,  Nancy Bump  1 ,  Sai M Pulukuri  1 ,  Steve Langston  1 ,  Stephen Tirrell  1 ,  Mike Kuranda  1 ,  Petter Veiby  1 ,  John Newcomb  1 ,  Ping Li  1 ,  Jing Tao Wu  1 ,  Josh Powe  1 ,  Lawrence R Dick  1 ,  Paul Greenspan  1 ,  Katherine Galvin  1 ,  Mark Manfredi  1 ,  Chris Claiborne  1 ,  Benjamin S Amidon  1 ,  Neil F Bence  1
Affiliations
  • 1. Takeda Pharmaceuticals Inc., Cambridge, Massachusetts, USA.
PMID: 29334375 DOI: 10.1038/nm.4474
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.

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