A selective inhibitor of the UFM1-activating enzyme, UBA5

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• 作者：Sara R. da Silva^a ; ^&dagger ; ; Stacey-Lynn Paiva^a ; ^&dagger ; ; Matthew Bancerz^b ; ^&dagger ; ; Mulu Geletu^b ; Andrew M. Lewis^b ; Jijun Chen^c ; Yafei Cai^c ; Julie L. Lukkarila^c ; Honglin Li^c ; Patrick T. Gunning^a ; ^b ; ^{patrick.gunning@utoronto.ca" class="auth_mail" title="E-mail the corresponding author}
• 关键词：UBA5 ; UFM1 ; Noncompetitive inhibition ; E1 activating enzyme ; Ubiquitin-like protein
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 September 2016
• 年：2016
• 卷：26
• 期：18
• 页码：4542-4547
• 全文大小：1320 K

文摘

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 50 μM) 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.