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Description

Dr. Peterson and Dr. Chernoff have devised a method to identify allosteric inhibitors of p21-activated kinases (Paks) that antagonize the conformational change required for Pak activation. The method may be extended to identify inhibitors of class I Paks, p21- and Rho-activated proteins, autoinhibited small GTPase effectors, and autoinhibited non-receptor serine/threonine kinases and phosphatases.

Kinase domains are remarkably conserved across diverse kinase families and, consequently, many chemical kinase inhibitors block multiple kinases. Indeed, the development of specific inhibitors of kinases is a major challange for the development of an appropriate drug, and targeting the Pak inhibitor domain may provide greater specificity than targeting the catalytic site. In this method, compounds are screened for the ability to inhibit the wild-type PAK but not a constitutively active form. Candidate allosteric inhibitors are those that inhibit the wild-type but not the constitutively active form.

Kinase assays need to be simple, inexpensive, and sensitive to the measured parameter but insensitive to solvent or biophysical properties of the compounds such as fluorescence. This invention provides a validated luminescence-based assay for kinase activity based on the measurement of residual ATP in the reaction following kinase-mediated ATP hydrolysis. This serves as a readout for the interaction of the PAK autoinhibitory domain with the kinase domain. This assay is remarkably homogeneous because the only manipulation is the addition of the detection mixture, and the assay is relatively insensitive to fluorescence or absorptive properties of individual compounds.

Compounds identified from this dual positive/negative selection screen may be further investigated for their inhibitory properties.

Applications

• Identification of allosteric kinase inhibitors

Advantages

• This assay is remarkably homogeneous because the only manipulation is the addition of the detection mixture, and the assay relatively insensitive to fluorescence or absorptive properties of individual compounds.

Relevant Articles

• Deacon SW, Beeser A, et al., "An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase," Chem Biol, 2008 15(4):322-31
• Peterson JR, Golemis EA, "Autoinhibited proteins as promising drug targets," J Cell Biochem 2004 Sep 1;93(1):68-73
• Kumar R, Gururaj AE, et al., "p21-activated kinases in cancer," Nat Rev Cancer, 2006 Jun;6(6):459-71
• Arias-Romero LE, Chernoff J., "A tale of two Paks," Biol Cell., 2008 Feb;100(2):97-108

For licensing information, contact

Clarissa Ceruti, PhD, MBA
Associate Director
Office of Corporate Alliances
Fox Chase Cancer Center
610 Old York Road, Room 407
Jenkintown, PA 19046
Tel.: 215-214-1546
Fax: 215-214-1440
clarissa.ceruti@fccc.edu