A selective small-molecule inhibitor of c-Jun N-terminal kinase 1

Ke Yao; Yong Yeon Cho; Ann M. Bode; Anuradha Vummenthala; Jewn Giew Park; Kangdong Liu; Yuan Ping Pang; Zigang Dong

doi:10.1016/j.febslet.2009.06.017

A selective small-molecule inhibitor of c-Jun N-terminal kinase 1

Ke Yao, Yong Yeon Cho, Ann M. Bode, Anuradha Vummenthala, Jewn Giew Park, Kangdong Liu, Yuan Ping Pang, Zigang Dong

The Hormel Institute

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

14 Scopus citations

Abstract

Indiscriminately suppressing total c-Jun N-terminal kinase (JNK) activity is not an appropriate strategy because each JNK appears to have a distinct function in cancer, asthma, diabetes, or Parkinson's disease. Herein, we report that 7-(6-N-phenylaminohexyl)amino-2H-anthra[1,9-cd]pyrazol-6-one (AV-7) inhibited JNK1 activity, but not JNK2 or JNK3. We found that ultraviolet B (UVB) induced c-Jun phosphorylation and sub-G1 accumulation in JNK2^-/- murine embryonic fibroblasts, which contain an abundance of JNK1, but not JNK2. These results demonstrate that AV-7 is an isoform selective small-molecule inhibitor of JNK1 activity, which might be developed as a therapeutic against diabetes. Structured summary: MINT-7148332: JNK3 (uniprotkb:P53779) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424). MINT-7148323: JNK2 (uniprotkb:P45984) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424). MINT-7148314: JNK1 (uniprotkb:P45983) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424).

Original language	English (US)
Pages (from-to)	2208-2212
Number of pages	5
Journal	FEBS Letters
Volume	583
Issue number	13
DOIs	https://doi.org/10.1016/j.febslet.2009.06.017
State	Published - Jul 7 2009

Bibliographical note

Funding Information:
This work is supported by a grant from the Minnesota Partnership for Biotechnology and Medical Genomics (L9046001101), The Hormel Foundation, the Mayo Foundation for Medical Education and Research, and the University of Minnesota Supercomputing Institute.

Keywords

AV-7
Small-molecule inhibitor
Sub-G1 accumulation
c-Jun N-terminal kinase inhibitor
c-Jun phosphorylation

UN SDGs

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

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10.1016/j.febslet.2009.06.017

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@article{2bdf9f5c4c704f09acb1993a91e0d63d,

title = "A selective small-molecule inhibitor of c-Jun N-terminal kinase 1",

abstract = "Indiscriminately suppressing total c-Jun N-terminal kinase (JNK) activity is not an appropriate strategy because each JNK appears to have a distinct function in cancer, asthma, diabetes, or Parkinson's disease. Herein, we report that 7-(6-N-phenylaminohexyl)amino-2H-anthra[1,9-cd]pyrazol-6-one (AV-7) inhibited JNK1 activity, but not JNK2 or JNK3. We found that ultraviolet B (UVB) induced c-Jun phosphorylation and sub-G1 accumulation in JNK2-/- murine embryonic fibroblasts, which contain an abundance of JNK1, but not JNK2. These results demonstrate that AV-7 is an isoform selective small-molecule inhibitor of JNK1 activity, which might be developed as a therapeutic against diabetes. Structured summary: MINT-7148332: JNK3 (uniprotkb:P53779) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424). MINT-7148323: JNK2 (uniprotkb:P45984) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424). MINT-7148314: JNK1 (uniprotkb:P45983) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424).",

keywords = "AV-7, Small-molecule inhibitor, Sub-G1 accumulation, c-Jun N-terminal kinase inhibitor, c-Jun phosphorylation",

author = "Ke Yao and Cho, {Yong Yeon} and Bode, {Ann M.} and Anuradha Vummenthala and Park, {Jewn Giew} and Kangdong Liu and Pang, {Yuan Ping} and Zigang Dong",

note = "Funding Information: This work is supported by a grant from the Minnesota Partnership for Biotechnology and Medical Genomics (L9046001101), The Hormel Foundation, the Mayo Foundation for Medical Education and Research, and the University of Minnesota Supercomputing Institute.",

year = "2009",

month = jul,

day = "7",

doi = "10.1016/j.febslet.2009.06.017",

language = "English (US)",

volume = "583",

pages = "2208--2212",

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TY - JOUR

T1 - A selective small-molecule inhibitor of c-Jun N-terminal kinase 1

AU - Yao, Ke

AU - Cho, Yong Yeon

AU - Bode, Ann M.

AU - Vummenthala, Anuradha

AU - Park, Jewn Giew

AU - Liu, Kangdong

AU - Pang, Yuan Ping

AU - Dong, Zigang

N1 - Funding Information: This work is supported by a grant from the Minnesota Partnership for Biotechnology and Medical Genomics (L9046001101), The Hormel Foundation, the Mayo Foundation for Medical Education and Research, and the University of Minnesota Supercomputing Institute.

PY - 2009/7/7

Y1 - 2009/7/7

N2 - Indiscriminately suppressing total c-Jun N-terminal kinase (JNK) activity is not an appropriate strategy because each JNK appears to have a distinct function in cancer, asthma, diabetes, or Parkinson's disease. Herein, we report that 7-(6-N-phenylaminohexyl)amino-2H-anthra[1,9-cd]pyrazol-6-one (AV-7) inhibited JNK1 activity, but not JNK2 or JNK3. We found that ultraviolet B (UVB) induced c-Jun phosphorylation and sub-G1 accumulation in JNK2-/- murine embryonic fibroblasts, which contain an abundance of JNK1, but not JNK2. These results demonstrate that AV-7 is an isoform selective small-molecule inhibitor of JNK1 activity, which might be developed as a therapeutic against diabetes. Structured summary: MINT-7148332: JNK3 (uniprotkb:P53779) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424). MINT-7148323: JNK2 (uniprotkb:P45984) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424). MINT-7148314: JNK1 (uniprotkb:P45983) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424).

AB - Indiscriminately suppressing total c-Jun N-terminal kinase (JNK) activity is not an appropriate strategy because each JNK appears to have a distinct function in cancer, asthma, diabetes, or Parkinson's disease. Herein, we report that 7-(6-N-phenylaminohexyl)amino-2H-anthra[1,9-cd]pyrazol-6-one (AV-7) inhibited JNK1 activity, but not JNK2 or JNK3. We found that ultraviolet B (UVB) induced c-Jun phosphorylation and sub-G1 accumulation in JNK2-/- murine embryonic fibroblasts, which contain an abundance of JNK1, but not JNK2. These results demonstrate that AV-7 is an isoform selective small-molecule inhibitor of JNK1 activity, which might be developed as a therapeutic against diabetes. Structured summary: MINT-7148332: JNK3 (uniprotkb:P53779) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424). MINT-7148323: JNK2 (uniprotkb:P45984) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424). MINT-7148314: JNK1 (uniprotkb:P45983) phosphorylates (MI:0217) c-JUN (uniprotkb:P05412) by protein kinase assay (MI:0424).

KW - AV-7

KW - Small-molecule inhibitor

KW - Sub-G1 accumulation

KW - c-Jun N-terminal kinase inhibitor

KW - c-Jun phosphorylation

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DO - 10.1016/j.febslet.2009.06.017

M3 - Article

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AN - SCOPUS:67649311246

SN - 0014-5793

VL - 583

SP - 2208

EP - 2212

JO - FEBS Letters

JF - FEBS Letters

IS - 13

ER -

A selective small-molecule inhibitor of c-Jun N-terminal kinase 1

Abstract

Bibliographical note

Keywords

UN SDGs

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