title: A selective inhibitor of the UFM1-activating enzyme, UBA5.
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.
authors: Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
authors: Sara R
authors: SR
authors: da Silva
authors: Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
authors: Stacey-Lynn
authors: SL
authors: Paiva
authors: Department of Chemical and Physical Sciences, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada.
authors: Matthew
authors: M
authors: Bancerz
authors: Department of Chemical and Physical Sciences, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada.
authors: Mulu
authors: M
authors: Geletu
authors: Department of Chemical and Physical Sciences, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada.
authors: Andrew M
authors: AM
authors: Lewis
authors: Department of Biochemistry and Molecular Biology, Georgia Regents University Cancer Center, Augusta, GA 30912, USA.
authors: Jijun
authors: J
authors: Chen
authors: Department of Biochemistry and Molecular Biology, Georgia Regents University Cancer Center, Augusta, GA 30912, USA.
authors: Yafei
authors: Y
authors: Cai
authors: Department of Biochemistry and Molecular Biology, Georgia Regents University Cancer Center, Augusta, GA 30912, USA.
authors: Julie L
authors: JL
authors: Lukkarila
authors: Department of Biochemistry and Molecular Biology, Georgia Regents University Cancer Center, Augusta, GA 30912, USA.
authors: Honglin
authors: H
authors: Li
authors: 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.
authors: Patrick T
authors: PT
authors: Gunning
mesh_terms: D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C502095:UBA5 protein, human; D044764:Ubiquitin-Activating Enzymes
keywords: E1 activating enzyme; Noncompetitive inhibition; UBA5; UFM1; Ubiquitin-like protein