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Nat Med. 2018 Feb;24(2):186-193. doi: 10.1038/nm.4474. Epub 2018 Jan 15.

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

Author information

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.

PMID:
29334375
DOI:
10.1038/nm.4474
[Indexed for MEDLINE]

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