Journal Article

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

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

2018

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 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