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PMID: 18420139 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase.

Chemistry & biology ·Vol. 15 ·No. 4 ·2008-04-00 ·Pages 322-31

Deacon SW, Beeser A, Fukui JA, Rennefahrt UE, Myers C, Chernoff J, Peterson JR

Abstract

Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric inhibitors targeting Pak1 activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.

MeSH Terms
Animals Disulfides/chemistry,metabolism,pharmacology Drug Evaluation, Preclinical/methods Enzyme Activation/drug effects Fibroblasts/drug effects,metabolism Homeostasis/drug effects Isoenzymes/antagonists & inhibitors,metabolism Mice Naphthols/chemistry,metabolism,pharmacology Platelet-Derived Growth Factor/metabolism Protein Conformation/drug effects Protein Kinase Inhibitors/metabolism,pharmacology Small Molecule Libraries/metabolism,pharmacology Substrate Specificity p21-Activated Kinases/antagonists & inhibitors,metabolism
Chemicals
Disulfides IPA-3 compound Isoenzymes Naphthols Platelet-Derived Growth Factor Protein Kinase Inhibitors Small Molecule Libraries p21-Activated Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Deacon Sean W
Basic Sciences Division, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Beeser Alexander
Fukui Jami A
Rennefahrt Ulrike E E
Myers Cynthia
Chernoff Jonathan
Peterson Jeffrey R
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Article Info
Journal
Chemistry & biology
Abbr.
Chem Biol
ISSN
1074-5521
DOI
10.1016/j.chembiol.2008.03.005
Published
2008-04-00
Pages
322-31
Language
English
Region
United States
NLM ID
9500160
PMCID
PMC4353635
Subset
IM
Grants
NCI NIH HHS · R01 CA117884 · United States
NCI NIH HHS · CA009035 · United States
NCI NIH HHS · CA006927 · United States
NCI NIH HHS · R01-CA117884 · United States
NCI NIH HHS · P30 CA006927 · United States
NCI NIH HHS · T32 CA009035 · United States
Corrections
CommentIn
PMID: 18420134
External Links
PubMed source DOI: 10.1016/j.chembiol.2008.03.005 PMC Full Text View journal details
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