A selective inhibitor of the UFM1-activating enzyme, UBA5

Sara R. da Silva, Stacey Lynn Paiva, Matthew Bancerz, Mulu Geletu, Andrew M. Lewis, Jijun Chen, Yafei Cai, Julie L. Lukkarila, Honglin Li, Patrick T. Gunning

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)4542-4547
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number18
DOIs
StatePublished - Jan 1 2016

Fingerprint

Ubiquitin
Cells
Cell Proliferation
Organometallics
Enzymes
Scaffolds
Adenosine
Disease Progression
Zinc
Neoplasms
Cell Survival
Proteins
Phosphotransferases
Molecules
cyclen

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

da Silva, S. R., Paiva, S. L., Bancerz, M., Geletu, M., Lewis, A. M., Chen, J., ... Gunning, P. T. (2016). A selective inhibitor of the UFM1-activating enzyme, UBA5. Bioorganic and Medicinal Chemistry Letters, 26(18), 4542-4547. https://doi.org/10.1016/j.bmcl.2015.10.015

A selective inhibitor of the UFM1-activating enzyme, UBA5. / 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.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 18, 01.01.2016, p. 4542-4547.

Research output: Contribution to journalArticle

da Silva, SR, Paiva, SL, Bancerz, M, Geletu, M, Lewis, AM, Chen, J, Cai, Y, Lukkarila, JL, Li, H & Gunning, PT 2016, 'A selective inhibitor of the UFM1-activating enzyme, UBA5', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 18, pp. 4542-4547. https://doi.org/10.1016/j.bmcl.2015.10.015
da Silva SR, Paiva SL, Bancerz M, Geletu M, Lewis AM, Chen J et al. A selective inhibitor of the UFM1-activating enzyme, UBA5. Bioorganic and Medicinal Chemistry Letters. 2016 Jan 1;26(18):4542-4547. https://doi.org/10.1016/j.bmcl.2015.10.015
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. / A selective inhibitor of the UFM1-activating enzyme, UBA5. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 18. pp. 4542-4547.
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