1. Academic Validation
  2. 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.
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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