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A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment
Nature medicine, 2018-02, Vol.24 (2), p.186-193
2018
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Autor(en) / Beteiligte
Titel
A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment
Ist Teil von
  • Nature medicine, 2018-02, Vol.24 (2), p.186-193
Ort / Verlag
New York: Nature Publishing Group US
Erscheinungsjahr
2018
Quelle
MEDLINE
Beschreibungen/Notizen
  • Hyer et al . generate a potent and specific small-molecule inhibitor of the E1 ubiquitin-activating enzyme UBE1 that has antitumor activity in mice against a wide variety of tumor types. 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.
Sprache
Englisch
Identifikatoren
ISSN: 1078-8956
eISSN: 1546-170X
DOI: 10.1038/nm.4474
Titel-ID: cdi_proquest_journals_1999171219
Format
–
Schlagworte
631/154/555, 631/67/1059/153, 631/67/1059/99, Animals, Anticancer properties, Antineoplastic agents, Antitumor activity, Biomedicine, Cancer, Cancer Research, Cancer therapies, Cell cycle, Cell Line, Tumor, Conjugation, Deoxyribonucleic acid, DNA, DNA damage, DNA Damage - drug effects, DNA repair, DNA Repair - drug effects, Enzymes, Genetic aspects, Health aspects, Homeostasis, Humans, Imides - pharmacology, Immunomodulation, Infectious Diseases, Inhibitors, Interrogation, Metabolic Diseases, Mice, Modulators, Molecular Medicine, Molecules, Neoplasms - drug therapy, Neoplasms - genetics, Neoplasms - pathology, Neurosciences, Nucleosides - pharmacology, Physiological aspects, Proteasome Endopeptidase Complex - chemistry, Proteasome Endopeptidase Complex - drug effects, Proteasome Endopeptidase Complex - genetics, Proteasome inhibitors, Proteasomes, Protein Binding, Signaling, Small Molecule Libraries - pharmacology, Sulfonamides - pharmacology, Ubiquitin, Ubiquitin - antagonists & inhibitors, Ubiquitin - chemistry, Ubiquitin - genetics, Ubiquitin-Activating Enzymes - antagonists & inhibitors, Ubiquitin-Activating Enzymes - chemistry, Ubiquitin-Activating Enzymes - genetics, Ubiquitin-proteasome system, Xenograft Model Antitumor Assays, Xenografts

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