p21 (RAC1) activated kinase 1 | PAKA subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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p21 (RAC1) activated kinase 1

target has curated data in GtoImmuPdb

Target id: 2133

Nomenclature: p21 (RAC1) activated kinase 1

Abbreviated Name: PAK1

Family: PAKA subfamily

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 553 11q13-q14 PAK1 p21 (RAC1) activated kinase 1
Mouse - 544 7 E2 Pak1 p21 (RAC1) activated kinase 1
Rat - 544 1 q32 Pak1 p21 (RAC1) activated kinase 1
Previous and Unofficial Names
alpha-PAK | p21 (CDKN1A)-activated kinase 1 | p21-activated kinase 1 | p65-PAK | p68-PAK | protein kinase MUK2 | p21 protein (Cdc42/Rac)-activated kinase 1
Database Links
BRENDA 2.7.11.1
CATH/Gene3D 3.90.810.10
ChEMBL Target CHEMBL4600 (Hs), CHEMBL4295682 (Mm), CHEMBL3580528 (Rn)
Ensembl Gene ENSG00000149269 (Hs), ENSMUSG00000030774 (Mm), ENSRNOG00000029784 (Rn)
Entrez Gene 5058 (Hs), 18479 (Mm), 29431 (Rn)
Human Protein Atlas ENSG00000149269 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:5058 (Hs), mmu:18479 (Mm), rno:29431 (Rn)
OMIM 602590 (Hs)
Pharos Q13153 (Hs)
RefSeq Nucleotide NM_001128620 (Hs), NM_011035 (Mm), NM_017198 (Rn)
RefSeq Protein NP_001122092 (Hs), NP_035165 (Mm), NP_058894 (Rn)
SynPHARM 83171 (in complex with FRAX597)
83160 (in complex with PF-3758309)
UniProtKB Q13153 (Hs), O88643 (Mm), P35465 (Rn)
Wikipedia PAK1 (Hs)
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF HUMAN SERINE/THREONINE KINASE PAK1
PDB Id:  1F3M
Resolution:  2.3Å
Species:  Human
References:  8
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of PAK1 kinase domain with ruthenium complex lambda-FL172
PDB Id:  3FXZ
Resolution:  1.64Å
Species:  Human
References:  11
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure of PAK1 in complex with PF-3758309.
PDB Id:  4O0R
Ligand:  PF-3758309
Resolution:  2.4Å
Species:  Human
References:  13
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor.
PDB Id:  4EQC
Ligand:  FRAX597
Resolution:  2.01Å
Species:  Human
References:  9
Enzyme Reaction
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PF-3758309 Hs Inhibition 7.4 pKi 13
⤷ pKi 7.4 (Ki 3.6x10-8 M) [13]
Il-94 Hs Inhibition 7.4 pKi 1
⤷ pKi 7.4 (Ki 3.68x10-8 M) [1]
compound 4 [PMID: 24432870] Hs Inhibition 5.3 – 5.3 pKi 7,13
⤷ pKi 5.3 – 5.3 (Ki 5.42x10-6 – 4.5x10-6 M) [7,13]
RKI-1447 Hs Inhibition >9.0 pIC50 12
⤷ pIC50 >9.0 (IC50 <1x10-9 M) [12]
FRAX597 Hs Inhibition 8.1 pIC50 9
⤷ pIC50 8.1 (IC50 8x10-9 M) [9]
FRAX486 Hs Inhibition 8.1 pIC50 6
⤷ pIC50 8.1 (IC50 8.25x10-9 M) [6]
compound 1 [PMID: 20005102] Hs Inhibition 7.3 pIC50 10
⤷ pIC50 7.3 (IC50 3.1x10-8 M) [10]
IPA-3 Hs Inhibition 5.6 pIC50 5
⤷ pIC50 5.6 (IC50 2.5x10-6 M) [5]
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 3 [PMID: 26191365] Hs Negative 8.1 pKd 7
⤷ pKd 8.1 (Kd 7x10-9 M) [7]
Description: Binding affinity constant for the unphosphorylated kinase.
DiscoveRx KINOMEscan® screen
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: 4,14
Key to terms and symbols Click column headers to sort
Target used in screen: PAK1
Ligand Sp. Type Action Value Parameter
staurosporine Hs Inhibitor Inhibition 9.2 pKd
lestaurtinib Hs Inhibitor Inhibition 7.5 pKd
neratinib Hs Inhibitor Inhibition 6.7 pKd
tamatinib Hs Inhibitor Inhibition 6.6 pKd
GSK690693 Hs Inhibitor Inhibition 6.3 pKd
NVP-TAE684 Hs Inhibitor Inhibition 6.2 pKd
PLX-4720 Hs Inhibitor Inhibition 5.8 pKd
A-674563 Hs Inhibitor Inhibition 5.8 pKd
midostaurin Hs Inhibitor Inhibition 5.7 pKd
KW-2449 Hs Inhibitor Inhibition 5.7 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
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 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: ...2
Key to terms and symbols Click column headers to sort
Target used in screen: nd/PAK1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 1.6
K-252a Hs Inhibitor Inhibition 4.6
bosutinib Hs Inhibitor Inhibition 11.7
SB 218078 Hs Inhibitor Inhibition 23.6
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 29.0
midostaurin Hs Inhibitor Inhibition 35.1
alsterpaullone Hs Inhibitor Inhibition 36.7
alsterpaullone 2-cyanoethyl Hs Inhibitor Inhibition 52.1
indirubin derivative E804 Hs Inhibitor Inhibition 71.3
JAK3 inhibitor VI Hs Inhibitor Inhibition 78.7
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
PAK1 is reported to modulate a pro-inflammatory PPARγ/NF-κB cascade in intestinal inflammation, that may be relevant in inflammatory bowel disease and colitis-associated cancer [3].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0031295 T cell costimulation TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 5 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0031295 T cell costimulation TAS
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
GO:0050852 T cell receptor signaling pathway TAS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0031295 T cell costimulation TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 5 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0031295 T cell costimulation TAS
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
GO:0050852 T cell receptor signaling pathway TAS

References

Show »

1. Abdel-Magid AF. (2013) PAK1: A Therapeutic Target for Cancer Treatment. ACS Med Chem Lett, 4 (5): 431-2. [PMID:24900689]

2. 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]

3. Dammann K, Khare V, Lang M, Claudel T, Harpain F, Granofszky N, Evstatiev R, Williams JM, Pritchard DM, Watson A et al.. (2015) PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation. Biochim. Biophys. Acta, 1853 (10 Pt A): 2349-60. [PMID:26036343]

4. 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]

5. 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 (4): 322-31. [PMID:18420139]

6. Dolan BM, Duron SG, Campbell DA, Vollrath B, Shankaranarayana Rao BS, Ko HY, Lin GG, Govindarajan A, Choi SY, Tonegawa S. (2013) Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc. Natl. Acad. Sci. U.S.A., 110 (14): 5671-6. [PMID:23509247]

7. Karpov AS, Amiri P, Bellamacina C, Bellance MH, Breitenstein W, Daniel D, Denay R, Fabbro D, Fernandez C, Galuba I et al.. (2015) Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor. ACS Med Chem Lett, 6 (7): 776-81. [PMID:26191365]

8. 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 (3): 387-97. [PMID:10975528]

9. Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, Duron S, Campbell D, Chernoff J, Field J et al.. (2013) FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J. Biol. Chem., 288 (40): 29105-14. [PMID:23960073]

10. 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]

11. Maksimoska J, Feng L, Harms K, Yi C, Kissil J, Marmorstein R, Meggers E. (2008) Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes. J. Am. Chem. Soc., 130 (47): 15764-5. [PMID:18973295]

12. Pireddu R, Forinash KD, Sun NN, Martin MP, Sung SS, Alexander B, Zhu JY, Guida WC, Schönbrunn E, Sebti SM et al.. (2012) Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm, 3 (6): 699-709. [PMID:23275831]

13. Staben ST, Feng JA, Lyle K, Belvin M, Boggs J, Burch JD, Chua CC, Cui H, DiPasquale AG, Friedman LS et al.. (2014) Back pocket flexibility provides group II p21-activated kinase (PAK) selectivity for type I 1/2 kinase inhibitors. J. Med. Chem., 57 (3): 1033-45. [PMID:24432870]

14. 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]

How to cite this page

PAKA subfamily: p21 (RAC1) activated kinase 1. Last modified on 15/02/2017. Accessed on 29/09/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2133.