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p21 (RAC1) activated kinase 1

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Target id: 2133

Nomenclature: p21 (RAC1) activated kinase 1

Abbreviated Name: PAK1

Family: PAKA subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 545 11q13.5-q14.1 PAK1 p21 (RAC1) activated kinase 1
Mouse - 545 7 53.57 cM Pak1 p21 (RAC1) activated kinase 1
Rat - 544 1q32 Pak1 p21 (RAC1) activated kinase 1
Previous and Unofficial Names Click here for help
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 Click here for help
Alphafold Q13153 (Hs), O88643 (Mm), P35465 (Rn)
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 Click here for help
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:  9
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:  12
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:  14
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:  10
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
PF-3758309 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pKi 14
⤷ pKi 7.4 (Ki 3.6x10-8 M) [14]
Il-94 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.4 pKi 1
⤷ pKi 7.4 (Ki 3.68x10-8 M) [1]
compound 4 [PMID: 24432870] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.3 – 5.3 pKi 8,14
⤷ pKi 5.3 – 5.3 (Ki 5.42x10-6 – 4.5x10-6 M) [8,14]
RKI-1447 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >9.0 pIC50 13
⤷ pIC50 >9.0 (IC50 <1x10-9 M) [13]
FRAX597 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 10
⤷ pIC50 8.1 (IC50 8x10-9 M) [10]
FRAX486 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 7
⤷ pIC50 8.1 (IC50 8.25x10-9 M) [7]
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 11
⤷ pIC50 7.3 (IC50 3.1x10-8 M) [11]
IPA-3 Small molecule or natural product Primary target of this compound Hs Inhibition 5.6 pIC50 6
⤷ pIC50 5.6 (IC50 2.5x10-6 M) [6]
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] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Negative 8.1 pKd 8
⤷ pKd 8.1 (Kd 7x10-9 M) [8]
Description: Binding affinity constant for the unphosphorylated kinase.
BJG-05-039 Small molecule or natural product Hs Negative 6.6 pIC50 3
⤷ pIC50 6.6 (IC50 2.33x10-7 M) [3]
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: 5,15
Key to terms and symbols Click column headers to sort
Target used in screen: PAK1
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.2 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.5 pKd
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 6.7 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.6 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.2 pKd
PLX-4720 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.8 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.8 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.7 pKd
KW-2449 Small molecule or natural product 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 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: ...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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.6
K-252a Small molecule or natural product Hs Inhibitor Inhibition 4.6
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 11.7
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 23.6
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 29.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 35.1
alsterpaullone Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 36.7
alsterpaullone 2-cyanoethyl Small molecule or natural product Hs Inhibitor Inhibition 52.1
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 71.3
JAK3 inhibitor VI Small molecule or natural product 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 [4].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling

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. Chow HY, Karchugina S, Groendyke BJ, Toenjes S, Hatcher J, Donovan KA, Fischer ES, Abalakov G, Faezov B, Dunbrack R et al.. (2022) Development and Utility of a PAK1-Selective Degrader. J Med Chem, 65 (23): 15627-15641. [PMID:36416208]

4. 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]

5. 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]

6. 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]

7. 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 USA, 110 (14): 5671-6. [PMID:23509247]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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 28/11/2022. Accessed on 11/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2133.