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

doi:10.1016/j.bmcl.2015.10.015

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

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

17 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 language	English (US)
Pages (from-to)	4542-4547
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2015.10.015
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2015.10.015

Cite this

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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 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.",

keywords = "E1 activating enzyme, Noncompetitive inhibition, UBA5, UFM1, Ubiquitin-like protein",

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

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd",

year = "2016",

doi = "10.1016/j.bmcl.2015.10.015",

language = "English (US)",

volume = "26",

pages = "4542--4547",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - A selective inhibitor of the UFM1-activating enzyme, UBA5

AU - da Silva, Sara R.

AU - Paiva, Stacey Lynn

AU - Bancerz, Matthew

AU - Geletu, Mulu

AU - Lewis, Andrew M.

AU - Chen, Jijun

AU - Cai, Yafei

AU - Lukkarila, Julie L.

AU - Li, Honglin

AU - Gunning, Patrick T.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - E1 activating enzyme

KW - Noncompetitive inhibition

KW - UBA5

KW - UFM1

KW - Ubiquitin-like protein

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DO - 10.1016/j.bmcl.2015.10.015

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SN - 0960-894X

VL - 26

SP - 4542

EP - 4547

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 18

ER -

A selective inhibitor of the UFM1-activating enzyme, UBA5

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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