2. Academic Validation
  3. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment

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

Affiliation

  • 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.

Figures
Products