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 journalArticlepeer-review

9 Scopus citations

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

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

Fingerprint Dive into the research topics of 'A selective inhibitor of the UFM1-activating enzyme, UBA5'. Together they form a unique fingerprint.

Cite this