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Abstract
Post-translational modifications of cellular substrates with ubiquitin and ubiquitin-like proteins (UBLs), including ubiquitin, SUMOs, and neural precursor cell–expressed developmentally downregulated protein 8, play a central role in regulating many aspects of cell biology. The UBL conjugation cascade is initiated by a family of ATP-dependent enzymes termed E1 activating enzymes and executed by the downstream E2-conjugating enzymes and E3 ligases. Despite their druggability and their key position at the apex of the cascade, pharmacologic modulation of E1s with potent and selective drugs has remained elusive until 2009. Among the eight E1 enzymes identified so far, those initiating ubiquitylation (UBA1), SUMOylation (SAE), and neddylation (NAE) are the most characterized and are implicated in various aspects of cancer biology. To date, over 40 inhibitors have been reported to target UBA1, SAE, and NAE, including the NAE inhibitor pevonedistat, evaluated in more than 30 clinical trials. In this Review, we discuss E1 enzymes, the rationale for their therapeutic targeting in cancer, and their different inhibitors, with emphasis on the pharmacologic properties of adenosine sulfamates and their unique mechanism of action, termed substrate-assisted inhibition. Moreover, we highlight other less-characterized E1s—UBA6, UBA7, UBA4, UBA5, and autophagy-related protein 7—and the opportunities for targeting these enzymes in cancer.
Significance Statement The clinical successes of proteasome inhibitors in cancer therapy and the emerging resistance to these agents have prompted the exploration of other signaling nodes in the ubiquitin-proteasome system including E1 enzymes. Therefore, it is crucial to understand the biology of different E1 enzymes, their roles in cancer, and how to translate this knowledge into novel therapeutic strategies with potential implications in cancer treatment.
Footnotes
This work was supported by the Leukemia & Lymphoma Society of Canada, the Canadian Institutes of Health Research (CIHR), the Princess Margaret Cancer Centre Foundation, and the Ontario Ministry of Health and Long-Term Care. A.D.S. holds the Ronald N. Buick Chair in Oncology Research. S.H.B. was supported by the Ontario Trillium Scholarship, Department of Medical Biophysics Fellowship, Graduate Studies Endowment Fund (GSEF) Scholarship, and Queen Elizabeth II Scholarship from the Faculty of Medicine, University of Toronto, Canada.
A.D.S. has received honorariums or consulting fees from Novartis, Jazz, Otsuka, and Takeda Pharmaceuticals and research support from Medivir AB and Takeda Pharmaceuticals. A.D.S. owns stock in Abbvie Pharmaceuticals and is named on a patent application for the use of DNT cells for the treatment of leukemia.
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- Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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