Chem Biol. 2008 Apr;15(4):322-31.

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

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

Source

Basic Sciences Division, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

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.

Comment in

Chem Biol. 2008 Apr;15(4):305-6.

PMID:: 18420139; [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances, Grant Support

Publication Types

MeSH Terms

Substances

Grant Support

LinkOut - more resources

Full Text Sources

Other Literature Sources

COS Scholar Universe

Supplemental Content

Related citations

PAK'n it in: identification of a selective PAK inhibitor. [Chem Biol. 2008]
PAK'n it in: identification of a selective PAK inhibitor.
Bokoch GM. Chem Biol. 2008 Apr; 15(4):305-6.
An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently. [Mol Cancer Ther. 2009]
An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently.
Viaud J, Peterson JR. Mol Cancer Ther. 2009 Sep; 8(9):2559-65. Epub 2009 Sep 1.
Development of a fluorescent-tagged kinase assay system for the detection and characterization of allosteric kinase inhibitors. [J Am Chem Soc. 2009]
Development of a fluorescent-tagged kinase assay system for the detection and characterization of allosteric kinase inhibitors.
Simard JR, Getlik M, Grütter C, Pawar V, Wulfert S, Rabiller M, Rauh D. J Am Chem Soc. 2009 Sep 23; 131(37):13286-96.
Review Development of small-molecule inhibitors of the group I p21-activated kinases, emerging therapeutic targets in cancer. [Biochem Pharmacol. 2010]
Review Development of small-molecule inhibitors of the group I p21-activated kinases, emerging therapeutic targets in cancer.
Yi C, Maksimoska J, Marmorstein R, Kissil JL. Biochem Pharmacol. 2010 Sep 1; 80(5):683-9. Epub 2010 Mar 17.
Review Protein kinase inhibitors: contributions from structure to clinical compounds. [Q Rev Biophys. 2009]
Review Protein kinase inhibitors: contributions from structure to clinical compounds.
Johnson LN. Q Rev Biophys. 2009 Feb; 42(1):1-40. Epub 2009 Mar 19.

See reviews... See all...

Cited by 30 PubMed Central articles

P21-activated kinase 4 overexpression in metastatic gastric cancer patients. [Transl Oncol. 2011]
P21-activated kinase 4 overexpression in metastatic gastric cancer patients.
Ahn HK, Jang J, Lee J, Se Hoon P, Park JO, Park YS, Lim HY, Kim KM, Kang WK. Transl Oncol. 2011 Dec; 4(6):345-9. Epub 2011 Dec 1.
p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112. [PLoS One. 2011]
p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112.
Ye DZ, Jin S, Zhuo Y, Field J. PLoS One. 2011; 6(11):e27637. Epub 2011 Nov 11.
p21-activated kinases in Erbb2-positive breast cancer: A new therapeutic target? [Small Gtpases. 2010]
p21-activated kinases in Erbb2-positive breast cancer: A new therapeutic target?
Arias-Romero LE, Chernoff J. Small Gtpases. 2010 Sep; 1(2):124-128.

See all...

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
Compound (MeSH Keyword)
PubChem chemical compound records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Substance (MeSH Keyword)
PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

An isoform-selective, small-molecule inhibitor targets the autoregulatory mechan...
An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase.
Chem Biol. 2008 Apr ;15(4):322-31.

PubMed
Association of hypertension and hypokalemia with Cushing's syndrome caused by ec...
Association of hypertension and hypokalemia with Cushing's syndrome caused by ectopic ACTH secretion: a series of 58 cases.
Ann N Y Acad Sci. 2002 Sep ;970:134-44.

PubMed
The inhibitory effect of essential oils on herpes simplex virus type-1 replicati...
The inhibitory effect of essential oils on herpes simplex virus type-1 replication in vitro.
Microbiol Immunol. 2003 ;47(9):681-4.

PubMed
Case-only study of interactions between DNA repair genes (hMLH1, APEX1, MGMT, XR...
Case-only study of interactions between DNA repair genes (hMLH1, APEX1, MGMT, XRCC1 and XPD) and low-frequency electromagnetic fields in childhood acute leukemia.
Leuk Lymphoma. 2008 Dec ;49(12):2344-50.

PubMed
Psychology, public policy, and the evidence for alcohol intoxication.
Psychology, public policy, and the evidence for alcohol intoxication.
Am Psychol. 1983 Oct ;38(10):1070-7.

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Display Settings:

Send to: