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3-phosphoinositide dependent protein kinase 1

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Target id: 1519

Nomenclature: 3-phosphoinositide dependent protein kinase 1

Abbreviated Name: PDK1

Family: PDK1 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 556 16p13.3 PDPK1 3-phosphoinositide dependent protein kinase 1
Mouse - 559 17 A3.3 Pdpk1 3-phosphoinositide dependent protein kinase 1
Rat - 559 10q12 Pdpk1 3-phosphoinositide dependent protein kinase-1
Previous and Unofficial Names Click here for help
PkB kinase | protein kinase B kinase | 3-phosphoinositide dependent protein kinase-1
Database Links Click here for help
Alphafold O15530 (Hs), Q9Z2A0 (Mm), O55173 (Rn)
BRENDA 2.7.11.1
CATH/Gene3D 2.30.29.30
ChEMBL Target CHEMBL2534 (Hs)
Ensembl Gene ENSG00000140992 (Hs), ENSMUSG00000024122 (Mm), ENSRNOG00000006136 (Rn)
Entrez Gene 5170 (Hs), 18607 (Mm), 81745 (Rn)
Human Protein Atlas ENSG00000140992 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:5170 (Hs), mmu:18607 (Mm), rno:81745 (Rn)
OMIM 605213 (Hs)
Pharos O15530 (Hs)
RefSeq Nucleotide NM_001261816 (Hs), NM_011062 (Mm), NM_031081 (Rn)
RefSeq Protein NP_002604 (Hs), NP_001074242 (Mm), NP_035192 (Mm), NP_112343 (Rn)
SynPHARM 80784 (in complex with 7-hydroxystaurosporine)
UniProtKB O15530 (Hs), Q9Z2A0 (Mm), O55173 (Rn)
Wikipedia PDPK1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  PDK1 in complex with inhibitor MP7
PDB Id:  3NAX
Resolution:  1.75Å
Species:  Human
References:  13
Image of receptor 3D structure from RCSB PDB
Description:  HIGH RESOLUTION CRYSTAL STRUCTURE OF THE HUMAN PDK1 CATALYTIC DOMAIN
PDB Id:  1H1W
Resolution:  2.0Å
Species:  Human
References:  2
Image of receptor 3D structure from RCSB PDB
Description:  Structure of human PDK1 kinase domain in complex with UCN-01
PDB Id:  1OKZ
Ligand:  7-hydroxystaurosporine
Resolution:  2.51Å
Species:  Human
References:  8
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PHT-427 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 5.3 pKi 11
⤷ pKi 5.3 (Ki 5.2x10-6 M) [11]
Description: Assay using purified recombinant pleckstrin homology domain of human PDK1
GSK2334470 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.6 pIC50 10
⤷ pIC50 8.6 (IC50 2.51x10-9 M) [10]
OSU-03012 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.1 pIC50 18
⤷ pIC50 8.1 (IC50 9x10-9 M) [18]
BX-795 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 4
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [4]
Description: In a direct kinase activity measuring phosphorylation od a small peptide substrate mimetic
BX-912 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.6 pIC50 4
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [4]
Description: In a direct kinase activity measuring phosphorylation od a small peptide substrate mimetic
7-hydroxystaurosporine Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pIC50 14
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [14]
compound 1 [PMID: 20005102] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 9
⤷ pIC50 7.3 (IC50 5x10-8 M) [9]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 3,17
Key to terms and symbols Click column headers to sort
Target used in screen: PDPK1
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.8 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.5 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.9 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.2 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.2 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 5.6 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
erlotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
linifanib Small molecule or natural product Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM 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

Reference: 1,5
Key to terms and symbols Click column headers to sort
Target used in screen: PDK1/PDK1(PDPK1)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Small molecule or natural product Hs Inhibitor Inhibition 1.6 -1.0 0.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.4 0.5 0.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 10.6 27.0 4.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 19.3 3.0 0.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 21.8 2.0 1.0
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 27.0 3.0 1.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 46.9 6.0 2.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 63.2 6.0 6.0
Cdk4 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 66.1 75.0 29.0
Cdk2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 69.1 20.0 3.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
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].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
General Comments
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].

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

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. EMBO J, 21 (16): 4219-28. [PMID:12169624]

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. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

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. J Biol Chem, 280 (20): 19867-74. [PMID:15772071]

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. Biochem J, 451 (2): 313-28. [PMID:23398362]

6. Hanada M, Feng J, Hemmings BA. (2004) Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochim Biophys Acta, 1697 (1-2): 3-16. [PMID:15023346]

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. Diabetes, 61 (8): 1935-48. [PMID:22586579]

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. Biochem J, 375 (Pt 2): 255-62. [PMID:12892559]

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. Bioorg Med Chem Lett, 20 (2): 679-83. [PMID:20005102]

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. J Med Chem, 54 (6): 1871-95. [PMID:21341675]

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. Mol Cancer Ther, 9 (3): 706-17. [PMID:20197390]

12. Mora A, Komander D, van Aalten DM, Alessi DR. (2004) PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol, 15 (2): 161-70. [PMID:15209375]

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. J Biol Chem, 286 (8): 6433-48. [PMID:21118801]

14. Sato S, Fujita N, Tsuruo T. (2002) Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene, 21 (11): 1727-38. [PMID:11896604]

15. Shiojima I, Walsh K. (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res, 90 (12): 1243-50. [PMID:12089061]

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. Eur J Immunol, 45 (5): 1548-59. [PMID:25645675]

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. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

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. Cancer Res, 64 (12): 4309-18. [PMID:15205346]

How to cite this page

PDK1 family: 3-phosphoinositide dependent protein kinase 1. Last modified on 15/02/2017. Accessed on 19/09/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1519.