1. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment.
- Author
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Hyer ML, Milhollen MA, Ciavarri J, Fleming P, Traore T, Sappal D, Huck J, Shi J, Gavin J, Brownell J, Yang Y, Stringer B, Griffin R, Bruzzese F, Soucy T, Duffy J, Rabino C, Riceberg J, Hoar K, Lublinsky A, Menon S, Sintchak M, Bump N, Pulukuri SM, Langston S, Tirrell S, Kuranda M, Veiby P, Newcomb J, Li P, Wu JT, Powe J, Dick LR, Greenspan P, Galvin K, Manfredi M, Claiborne C, Amidon BS, and Bence NF
- Subjects
- Animals, Cell Line, Tumor, DNA Damage drug effects, DNA Repair drug effects, Humans, Imides pharmacology, Mice, Neoplasms genetics, Neoplasms pathology, Proteasome Endopeptidase Complex chemistry, Proteasome Endopeptidase Complex drug effects, Proteasome Endopeptidase Complex genetics, Protein Binding, Pyrazoles, Pyrimidines, Sulfides, Ubiquitin antagonists & inhibitors, Ubiquitin chemistry, Ubiquitin genetics, Ubiquitin-Activating Enzymes chemistry, Ubiquitin-Activating Enzymes genetics, Xenograft Model Antitumor Assays, Neoplasms drug therapy, Nucleosides pharmacology, Small Molecule Libraries pharmacology, Sulfonamides pharmacology, Ubiquitin-Activating Enzymes antagonists & inhibitors
- 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.
- Published
- 2018
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