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PkB kinase|protein kinase B kinase|3-phosphoinositide dependent protein kinase-1 Description: HIGH RESOLUTION CRYSTAL STRUCTURE OF THE HUMAN PDK1 CATALYTIC DOMAIN Download all structure-activity data for this target as a CSV file Description: Assay using purified recombinant pleckstrin homology domain of human PDK1 Description: In a direct kinase activity measuring phosphorylation od a small peptide substrate mimetic Description: In a direct kinase activity measuring phosphorylation od a small peptide substrate mimetic EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1 M and 10 M against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5 M against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform. http://www.millipore.com/techpublications/tech1/pf3036 http://www.reactionbiology.com/webapps/main/pages/kinase.aspx In addition to its role in oncology, in mouse studies, PDK1 is reported to play a part in regulating insulin sensitivity (and inhibiting adipose tissue inflammation), via the Pdk1/Foxo1 pathway and expression of Ccr2 [7]. In addition, as a downstream effector in PI3K signaling, PDK1 is implicated in transducing inhibitory signals on eosinophil effector function [16]. PDK1 phosphorylates and activates the AGC kinase members which are regulated by phosphatidylinositol 3-kinase (PI 3-kinase), including AKT, PKC, S6K and SGK [12]. The PDK1/AKT signaling pathway plays a key role in cancer cell growth, survival, and tumour angiogenesis and represents a promising target for oncology therapeutics [6,15]. 1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR.(2011)Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. 2. Biondi RM, Komander D, Thomas CC, Lizcano JM, Deak M, Alessi DR, van Aalten DM.(2002)High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site. 3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.(2011)Comprehensive analysis of kinase inhibitor selectivity. 4. Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J, Yuan S et al..(2005)Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. 5. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ.(2013)A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. 6. Hanada M, Feng J, Hemmings BA.(2004)Structure, regulation and function of PKB/AKT--a major therapeutic target. 7. Kawano Y, Nakae J, Watanabe N, Fujisaka S, Iskandar K, Sekioka R, Hayashi Y, Tobe K, Kasuga M, Noda T et al..(2012)Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance. 8. Komander D, Kular GS, Bain J, Elliott M, Alessi DR, Van Aalten DM.(2003)Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositide-dependent protein kinase-1) inhibition. 9. Lin H, Yamashita DS, Zeng J, Xie R, Verma S, Luengo JI, Rhodes N, Zhang S, Robell KA, Choudhry AE et al..(2010)2,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles. 10. Medina JR, Becker CJ, Blackledge CW, Duquenne C, Feng Y, Grant SW, Heerding D, Li WH, Miller WH, Romeril SP et al..(2011)Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors. 11. Meuillet EJ, Zuohe S, Lemos R, Ihle N, Kingston J, Watkins R, Moses SA, Zhang S, Du-Cuny L, Herbst R et al..(2010)Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. 12. Mora A, Komander D, van Aalten DM, Alessi DR.(2004)PDK1, the master regulator of AGC kinase signal transduction. 13. Nagashima K, Shumway SD, Sathyanarayanan S, Chen AH, Dolinski B, Xu Y, Keilhack H, Nguyen T, Wiznerowicz M, Li L et al..(2011)Genetic and pharmacological inhibition of PDK1 in cancer cells: characterization of a selective allosteric kinase inhibitor. 14. Sato S, Fujita N, Tsuruo T.(2002)Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). 15. Shiojima I, Walsh K.(2002)Role of Akt signaling in vascular homeostasis and angiogenesis. 16. Sturm EM, Parzmair GP, Radnai B, Frei RB, Sturm GJ, Hammer A, Schuligoi R, Lippe IT, Heinemann A.(2015)Phosphoinositide-dependent protein kinase 1 (PDK1) mediates potent inhibitory effects on eosinophils. 17. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al..(2010)Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. 18. Zhu J, Huang JW, Tseng PH, Yang YT, Fowble J, Shiau CW, Shaw YJ, Kulp SK, Chen CS.(2004)From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. PDK1 family: 3-phosphoinositide dependent protein kinase 1. Last modified on 15/02/2017. Accessed on 18/05/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1519.