Abstract
Protein kinases are among the most important drug targets; however the structural conservation of the ATP-binding pocket of kinases can lead to promiscuous inhibition of additional unintended kinase targets. Allosteric inhibitors that target less conserved regions of protein kinases represent an alternative approach that may provide more selective kinase inhibition. In this report, protocols are provided for the screening and identification of Pak1 inhibitors acting via an allosteric mechanism.
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References
Bain J, McLauchlan H, Elliott M, Cohen P (2003) The specificities of protein kinase inhibitors: an update. Biochem J 371:199–204
Deacon SW, Beeser A, Fukui JA, Rennefahrt UE, Myers C, Chernoff J, Peterson JR (2008) An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase. Chem Biol 15:322–331
Viaud J, Peterson JR (2009) An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently. Mol Cancer Ther 8:2559–2565
Eswaran J, Soundararajan M, Knapp S (2009) Targeting group II PAKs in cancer and metastasis. Cancer Metastasis Rev 28:209–217
Vadlamudi RK, Kumar R (2003) P21-activated kinases in human cancer. Cancer Metastasis Rev 22:385–393
Vadlamudi RK, Kumar R (2004) p21-activated kinase 1: an emerging therapeutic target. Cancer Treat Res 119:77–88
Kumar R, Gururaj AE, Barnes CJ (2006) p21-activated kinases in cancer. Nat Rev Cancer 6:459–471
Lei M, Lu W, Meng W, Parrini MC, Eck MJ, Mayer BJ, Harrison SC (2000) Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell 102: 387–397
Parrini MC, Lei M, Harrison SC, Mayer BJ (2002) Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1. Mol Cell 9:73–83
Strochlic TI, Viaud J, Rennefahrt UE, Anastassiadis T, Peterson JR (2010) Phosphoinositides are essential coactivators for p21-activated kinase 1. Mol Cell 40: 493–500
Gatti A, Huang Z, Tuazon PT, Traugh JA (1999) Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation. J Biol Chem 274: 8022–8028
Koresawa M, Okabe T (2004) High-throughput screening with quantitation of ATP consumption: a universal non-radioisotope, homogeneous assay for protein kinase. Assay Drug Dev Technol 2:153–160
Prowse CN, Hagopian JC, Cobb MH, Ahn NG, Lew J (2000) Catalytic reaction pathway for the mitogen-activated protein kinase ERK2. Biochemistry 39:6258–6266
Acknowledgments
This work described here was supported by a W.W. Smith Foundation Award and an American Cancer Society Scholar Award to J.R.P. and by a National Institutes of Health (NIH) award RO1 GM083025 to J.R.P.
J.V. was supported by a grant from the Fondation pour la Recherche Médicale.
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Viaud, J., Peterson, J.R. (2012). Identification of Allosteric Inhibitors of p21-Activated Kinase. In: Zheng, Y. (eds) Rational Drug Design. Methods in Molecular Biology, vol 928. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-008-3_6
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DOI: https://doi.org/10.1007/978-1-62703-008-3_6
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Publisher Name: Humana Press, Totowa, NJ
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Online ISBN: 978-1-62703-008-3
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