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

Hyer, Marc L ; Milhollen, Michael A ; Ciavarri, Jeff ; Fleming, Paul ; Traore, Tary ; Sappal, Darshan ; Huck, Jessica ; Shi, Judy ; Gavin, James ; Brownell, Jim ; Yang, Yu ; Stringer, Bradley ; Griffin, Robert ; Bruzzese, Frank ; Soucy, Teresa ; Duffy, Jennifer ; Rabino, Claudia ; Riceberg, Jessica ; Hoar, Kara ; Lublinsky, Anya ; Menon, Saurabh ; Sintchak, Michael ; Bump, Nancy ; Pulukuri, Sai M ; Langston, Steve ; Tirrell, Stephen ; Kuranda, Mike ; Veiby, Petter ; Newcomb, John ; Li, Ping ; Wu, Jing Tao ; Powe, Josh ; Dick, Lawrence R ; Greenspan, Paul ; Galvin, Katherine ; Manfredi, Mark ; Claiborne, Chris ; Amidon, Benjamin S ; Bence, Neil F

Nature medicine, 2018-02, Vol.24 (2), p.186-193 [Periódico revisado por pares]

United States: Nature Publishing Group

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A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment
Autor: Hyer, Marc L ; Milhollen, Michael A ; Ciavarri, Jeff ; Fleming, Paul ; Traore, Tary ; Sappal, Darshan ; Huck, Jessica ; Shi, Judy ; Gavin, James ; Brownell, Jim ; Yang, Yu ; Stringer, Bradley ; Griffin, Robert ; Bruzzese, Frank ; Soucy, Teresa ; Duffy, Jennifer ; Rabino, Claudia ; Riceberg, Jessica ; Hoar, Kara ; Lublinsky, Anya ; Menon, Saurabh ; Sintchak, Michael ; Bump, Nancy ; Pulukuri, Sai M ; Langston, Steve ; Tirrell, Stephen ; Kuranda, Mike ; Veiby, Petter ; Newcomb, John ; Li, Ping ; Wu, Jing Tao ; Powe, Josh ; Dick, Lawrence R ; Greenspan, Paul ; Galvin, Katherine ; Manfredi, Mark ; Claiborne, Chris ; Amidon, Benjamin S ; Bence, Neil F
Assuntos: Animals ; Anticancer properties ; Antimitotic agents ; Antineoplastic agents ; Antitumor activity ; Cancer ; Cancer therapies ; Cell cycle ; Cell Line, Tumor ; Conjugation ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA Damage - drug effects ; DNA repair ; DNA Repair - drug effects ; Drugs ; Enzymes ; Genetic aspects ; Health aspects ; Homeostasis ; Humans ; Imides - pharmacology ; Immunomodulation ; Inhibitors ; Interrogation ; Mice ; Modulators ; Molecules ; Neoplasms - drug therapy ; Neoplasms - genetics ; Neoplasms - pathology ; 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
É parte de: Nature medicine, 2018-02, Vol.24 (2), p.186-193
Descrição: 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.
Editor: United States: Nature Publishing Group
Idioma: Inglês

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

United States: Nature Publishing Group

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