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Protein conjugation with ubiquitin and ubiquitin-like small molecules, such as UFM1, is important for promoting cancer cell survival and proliferation. Herein, the development of the first selective micromolar inhibitor of the UBA5 E1 enzyme that initiates UFM1 protein conjugation is described. This organometallic inhibitor incorporates adenosine and zinc(II)cyclen within its core scaffold and inhibits UBA5 noncompetitively and selectively over other E1 enzymes and a panel of human kinases. Furthermore, this compound selectively impedes the cellular proliferation (above 50μM) of cancer cells containing higher levels of UBA5. This inhibitor may be used to further probe the intracellular role of the UFM1 pathway in disease progression.

Original publication

DOI

10.1016/j.bmcl.2015.10.015

Type

Journal article

Journal

Bioorganic & medicinal chemistry letters

Publication Date

08/10/2015

Volume

26

Pages

4542 - 4547

Addresses

Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.

Keywords

Cell Line, Tumor, Humans, Ubiquitin-Activating Enzymes, Enzyme Inhibitors