A selective inhibitor of the UFM1-activating enzyme, UBA5

作者：da Silva Sara R; Paiva Stacey Lynn; Bancerz Matthew; Geletu Mulu; Lewis Andrew M; Chen Jijun; Cai Yafei; Lukkarila Julie L; Li Honglin; Gunning Patrick T^*

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(18): 4542-4547.

DOI：10.1016/j.bmcl.2015.10.015

• UBA5
• UFM1
• Noncompetitive inhibition
• E1 activating enzyme
• Ubiquitin-like protein

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 mu M) 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.

• 出版日期2016-9-15