2. Academic Validation
  3. A selective inhibitor of the UFM1-activating enzyme, UBA5

A selective inhibitor of the UFM1-activating enzyme, UBA5

  • Bioorg Med Chem Lett. 2016 Sep 15;26(18):4542-4547. doi: 10.1016/j.bmcl.2015.10.015.
Sara R da Silva 1,  Stacey-Lynn Paiva 1,  Matthew Bancerz 2,  Mulu Geletu 2,  Andrew M Lewis 2,  Jijun Chen 3,  Yafei Cai 3,  Julie L Lukkarila 3,  Honglin Li 3,  Patrick T Gunning 4
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
  • 2 Department of Chemical and Physical Sciences, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada.
  • 3 Department of Biochemistry and Molecular Biology, Georgia Regents University Cancer Center, Augusta, GA 30912, USA.
  • 4 Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada; Department of Chemical and Physical Sciences, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada. Electronic address: patrick.gunning@utoronto.ca.
PMID: 27520940 DOI: 10.1016/j.bmcl.2015.10.015
Abstract

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.

Keywords

E1 activating enzyme; Noncompetitive inhibition; UBA5; UFM1; Ubiquitin-like protein.

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