PAK1

Summary

PAK1 (p21 (RAC1) activated kinase 1, HGNC:8590) is a protein-coding gene on chromosome 11q13.5-q14.1, encoding Serine/threonine-protein kinase PAK 1 (Q13153). Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes.

This gene encodes a family member of serine/threonine p21-activating kinases, known as PAK proteins. These proteins are critical effectors that link RhoGTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. This specific family member regulates cell motility and morphology. Mutations in this gene have been associated with macrocephaly, seizures, and speech delay. Overexpression of this gene is also reported in many cancer types, and particularly in breast cancer. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5058 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder with macrocephaly, seizures, and speech delay (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 164 total — 2 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 23 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002576

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8590
Approved symbol	PAK1
Name	p21 (RAC1) activated kinase 1
Location	11q13.5-q14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000149269
Ensembl biotype	protein_coding
OMIM	602590
Entrez	5058

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 43 protein_coding, 7 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000278568, ENST00000356341, ENST00000524847, ENST00000525542, ENST00000526103, ENST00000526910, ENST00000526968, ENST00000527457, ENST00000527535, ENST00000528203, ENST00000528592, ENST00000528633, ENST00000529248, ENST00000530358, ENST00000530617, ENST00000532711, ENST00000532991, ENST00000533285, ENST00000533468, ENST00000533568, ENST00000873292, ENST00000873293, ENST00000873294, ENST00000873295, ENST00000873296, ENST00000873297, ENST00000873298, ENST00000873299, ENST00000873300, ENST00000873301, ENST00000873302, ENST00000873303, ENST00000873304, ENST00000873305, ENST00000873306, ENST00000873307, ENST00000873308, ENST00000873309, ENST00000873310, ENST00000926600, ENST00000926601, ENST00000926602, ENST00000926603, ENST00000926604, ENST00000926605, ENST00000956798, ENST00000956799, ENST00000956800, ENST00000956801, ENST00000956802, ENST00000956803, ENST00000956804, ENST00000956805

RefSeq mRNA: 35 — MANE Select: NM_002576 NM_001128620, NM_001376268, NM_001376269, NM_001376270, NM_001376271, NM_001376272, NM_001376273, NM_001376274, NM_001376275, NM_001376276, NM_001376277, NM_001376278, NM_001376279, NM_001376280, NM_001376281, NM_001376282, NM_001376283, NM_001376284, NM_001376285, NM_001376286, NM_001376287, NM_001376288, NM_001376289, NM_001376290, NM_001376291, NM_001376292, NM_001376293, NM_001376294, NM_001376295, NM_001376301, NM_001376302, NM_001376303, NM_001376304, NM_001376305, NM_002576

CCDS: CCDS44687, CCDS8250, CCDS91544, CCDS91545

Canonical transcript exons

ENST00000356341 — 15 exons

Exon	Start	End
ENSE00000989704	77355668	77355842
ENSE00002141126	77322017	77323360
ENSE00002168503	77473552	77474094
ENSE00003475076	77340646	77340763
ENSE00003494664	77349239	77349287
ENSE00003514807	77337324	77337423
ENSE00003548604	77374328	77374365
ENSE00003559672	77358898	77359017
ENSE00003564321	77343819	77343931
ENSE00003568804	77353536	77353599
ENSE00003595091	77379894	77379994
ENSE00003606469	77332730	77332867
ENSE00003631938	77379241	77379388
ENSE00003634301	77336086	77336282
ENSE00003798409	77392331	77392541

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 99.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.5939 / max 1038.4322, expressed in 1733 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121418	34.0512	1659
121429	3.7930	903
121426	2.5682	879
121424	1.4905	696
121428	0.8704	385
121433	0.6599	292
121436	0.6102	319
121430	0.5786	341
121432	0.4760	265
121419	0.2738	124

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.29	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.63	gold quality
endothelial cell	CL:0000115	98.19	gold quality
monocyte	CL:0000576	98.19	gold quality
pons	UBERON:0000988	97.87	gold quality
cerebellar cortex	UBERON:0002129	97.61	gold quality
cerebellar hemisphere	UBERON:0002245	97.60	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.55	gold quality
right frontal lobe	UBERON:0002810	97.43	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.37	gold quality
prefrontal cortex	UBERON:0000451	97.36	gold quality
mononuclear cell	CL:0000842	97.18	gold quality
leukocyte	CL:0000738	97.15	gold quality
primary visual cortex	UBERON:0002436	96.83	gold quality
rectum	UBERON:0001052	96.56	gold quality
superior frontal gyrus	UBERON:0002661	96.56	gold quality
cerebellar vermis	UBERON:0004720	96.48	gold quality
cerebellum	UBERON:0002037	96.40	gold quality
frontal cortex	UBERON:0001870	96.22	gold quality
frontal lobe	UBERON:0016525	96.22	gold quality
cortical plate	UBERON:0005343	96.14	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.07	gold quality
blood	UBERON:0000178	96.04	gold quality
neocortex	UBERON:0001950	95.90	gold quality
mucosa of transverse colon	UBERON:0004991	95.77	gold quality
parietal lobe	UBERON:0001872	95.71	gold quality
occipital lobe	UBERON:0002021	95.71	gold quality
ganglionic eminence	UBERON:0004023	95.67	gold quality
frontal pole	UBERON:0002795	95.28	gold quality
granulocyte	CL:0000094	95.23	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	26.00
E-CURD-112	yes	24.68
E-HCAD-13	yes	20.70
E-HCAD-1	yes	17.24
E-MTAB-10042	yes	16.73
E-CURD-88	yes	13.89
E-MTAB-8410	yes	13.31
E-MTAB-6678	yes	8.71
E-MTAB-6386	no	261.41
E-MTAB-6142	no	184.34
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

90 targeting PAK1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-3975	99.62	65.97	697

Literature-anchored findings (GeneRIF, showing 40)

• Pak1 forms homodimers in vivo and its dimerization is regulated by the intracellular level of GTP-Cdc42 or GTP-Rac1 (PMID:11804587)
• PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway. (PMID:11948406)
• binding of the Rho family member Cdc42 to PLD1 and the subsequent stimulation of its enzymatic activity are distinct events (PMID:12011045)
• Pak1 interacts with and phosphorylates histone H3 and may thus influence the Pak1-histone H3 pathway, which in turn may influence mitotic events in breast cancer cells (PMID:12151336)
• FLNa may be essential for Pak1-induced cytoskeletal reorganization (PMID:12198493)
• Cdc42/Rac1-dependent activation of PAK may trigger early platelet shape change, at least in part through the regulation of cortactin binding to PAK. (PMID:12453877)
• p21-activated kinase 1 (PAK1) interacts with the Grb2 adapter protein to couple to growth factor signaling (PMID:12522133)
• phorbol ester induced cell migration is accompanied by selective and transient down-regulation of PAK1, which coincided with the formation of stress fibres. (PMID:12531429)
• role in phosphorylating Raf-1 regulates Raf-1 autoinhibition (PMID:12551923)
• results identify a novel signaling pathway linking estrogen action to Pak1 signaling, and Pak1 to FKHR, suggesting that Pak1 is an important mediator of estrogen’s cell survival functions (PMID:12560069)
• Activated Cdc42 at the leading edge of a neutrophil in culture helps orient the cell’s axis in a signaling complex with G beta gamma, PAK1, and PIXalpha. (PMID:12887916)
• G beta gamma binds PAK1 and, via PAK-associated PIX alpha, activates Cdc42 which, in turn, activates PAK1. In this pathway, PAK1 is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. (PMID:12887923)
• PAK1 regulates contact inhibition during epithelial wound healing. (PMID:12912914)
• PAK1 copy number gains were observed in 30% of ovarian carcinomas and PAK1 protein was expressed in 85% of tumors. PAK1 gains were associated with high grade. (PMID:12937139)
• Pak1 regulation of cyclin D1 expression might involve an NF-kappaB-dependent pathway; Pak1 is up-regulated in breast tumors (PMID:14530270)
• Tat induces actin cytoskeletal rearrangements through PAK1 in human umbilical vein endothelial cells (PMID:14694110)
• Phosphorylation of p41-ARC protein by p21-activated kinase 1. (PMID:14749719)
• PAK2 is constitutively activated in certain breast cancer cell lines and that this active PAK is mislocalized to atypical focal adhesions in the absence of high levels of activated Rho GTPases. (PMID:15047871)
• Src- & ROS-dependent PDK1 activation leads to site-specific PAK1 phosphorylation. This is critically important for PDGF-induced VSMC migration, a process integral to the vascular response to injury that leads to vessel occlusion & plaque formation. (PMID:15059930)
• Pak-1 has a role in human colorectal tumor invasiveness and motility (PMID:15161701)
• These results support a role for Pak1-mediated RhoGDI phosphorylation as a mechanism for Cdc42-mediated Rac activation, and suggest the possibility of Rac-induced positive feed-forward regulation of Rac activity. (PMID:15225553)
• PAK is a central regulator of endothelial permeability induced by multiple growth factors and cytokines via an effect on cell contractility (PMID:15333633)
• cell signaling kinase Pak1 is a novel regulator of glucose metabolism through its phosphorylation and regulation of PGM activity. (PMID:15378030)
• NF-kappaB- and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages (PMID:15561713)
• epithelial cell motility is modulated by integrin engagment through RhoA/ROCK and PAK1 (PMID:15611088)
• PAK1 negatively regulates the activity of NET1 (PMID:15684429)
• These findings define the nuclear localization signals (NLSs) of Pak1, its association with chromatin, and the resulting modulation of transcription, thus opening new avenues to further the search for nuclear Pak1 functions. (PMID:15749698)
• Pak1-SHARP interaction plays an essential role in enhancing the corepressor functions of SHARP, thereby modulating Notch1 signaling in human cancer cells. (PMID:15824732)
• PAK1 phosphorylation of tubulin cofactor B (TCoB)is essential for the polymerization of new microtubules. (PMID:15831477)
• The regulation of phosphorylation and function of Snail by Pak1 represents a novel mechanism by which a signaling kinase might contribute to the process of epithelial-mesenchymal transition. (PMID:15833848)
• Pak1-dependent Raf-1 phosphorylation regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association (PMID:15849194)
• PAK1 recruitment to the T cell-antigen-presenting cell interface required interaction with PIX. (PMID:15864311)
• 1.8 A resolution structure for the free PAK1 kinase domain was determined. (PMID:15893667)
• Data suggest that nischarin, in addition to regulating the p21-activated kinase (PAK) strand of Rac1 signaling, can also regulate other links in the web of Rac1 signaling pathways. (PMID:16002401)
• p21-activated kinase 1 has a role in the suppression of anoikis in breast cancer cells (PMID:16026643)
• the SH3 domain of betaPix specifically interacts with a proline-arginine motif (PxxxPR) present within the ubiquitin ligase Cbl and Pak1 kinase. Cbl and Pak1 compete for binding to betaPix. (PMID:16407834)
• Results show that PAK1 cooperate with different Rho effectors to regulate matrix contraction. (PMID:16449192)
• PI3K through p21-activated kinase 1 regulates FRA-1 proto-oncogene induction by cigarette smoke and the subsequent activation of the Elk1 and cAMP-response element-binding protein transcription factors (PMID:16490785)
• Myosin II-B resides in a complex with p21-activated kinase 1 (PAK1) and atypical protein kinase C (PKC) zeta (aPKCzeta) and the interaction between these proteins is EGF-dependent. (PMID:16611744)
• Our data support a role for Pak1, particular Pak1 localized to the nucleus, in ERalpha signaling and in tamoxifen resistance. (PMID:16705121)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pak1	ENSDARG00000103959
mus_musculus	Pak1	ENSMUSG00000030774
rattus_norvegicus	Pak1	ENSRNOG00000029784
drosophila_melanogaster	Pak	FBGN0267698

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), PAK5 (ENSG00000101349), STK24 (ENSG00000102572), STK3 (ENSG00000104375), MAP4K1 (ENSG00000104814), MAP3K8 (ENSG00000107968), MAP2K6 (ENSG00000108984), NEK4 (ENSG00000114904), STK25 (ENSG00000115694), NRK (ENSG00000123572), PAK4 (ENSG00000130669), STK26 (ENSG00000134602), TAOK3 (ENSG00000135090), PAK6 (ENSG00000137843), MINK1 (ENSG00000141503), TAOK2 (ENSG00000149930), TNIK (ENSG00000154310), TAOK1 (ENSG00000160551), MAP4K2 (ENSG00000168067), OXSR1 (ENSG00000172939), MAP3K19 (ENSG00000176601), PAK2 (ENSG00000180370), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Serine/threonine-protein kinase PAK 1 — Q13153 (reviewed: Q13153)

Alternative names: Alpha-PAK, p21-activated kinase 1, p65-PAK

All UniProt accessions (11): Q13153, B3KNX7, E9PJF8, E9PKH9, E9PM17, E9PMP2, E9PQW5, E9PRP6, H0YCG5, H0YCM0, H0YF55

UniProt curated annotations — full annotation on UniProt →

Function. Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as a GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at ‘Ser-338’ and ‘Ser-339’ resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at ‘Ser-246’ promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion. In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in F-actin stabilization. In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC). Along with GIT1, positively regulates microtubule nucleation during interphase. Phosphorylates FXR1, promoting its localization to stress granules and activity. Phosphorylates ILK on ‘Thr-173’ and ‘Ser-246’, promoting nuclear export of ILK.

Subunit / interactions. Homodimer; homodimerization results in autoinhibition. Active as monomer. Interacts with GIT1. Component of cytoplasmic complexes, which also contains PXN, ARHGEF7 and GIT1. Interacts with NISCH. Interacts with DVL1; mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering. Binds to the caspase-cleaved p110 isoform of CDC2L1 and CDC2L2, p110C, but not the full-length proteins. Interacts with ARHGEF7. Interacts tightly with GTP-bound but not GDP-bound CDC42/P21 and RAC1. Interacts with SCRIB. Interacts with PDPK1. Interacts (via kinase domain) with RAF1. Interacts with NCK1 and NCK2. Interacts with TBCB. Interacts with BRSK2. Interacts with SNAI1. Interacts with CIB1 isoform 2. Interacts with CIB1 (via N-terminal region); the interaction is direct, promotes PAK1 activity and occurs in a calcium-dependent manner. Interacts with INPP5K. Interacts with gamma-tubulin. Interacts with RHOU; the interaction promotes PAK1 activation.

Subcellular location. Cytoplasm. Cell junction. Focal adhesion. Cell projection. Lamellipodium. Cell membrane. Ruffle membrane. Invadopodium. Nucleus. Nucleoplasm. Chromosome. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Overexpressed in gastric cancer cells and tissues (at protein level).

Post-translational modifications. Autophosphorylated in trans, meaning that in a dimer, one kinase molecule phosphorylates the other one. Activated by autophosphorylation at Thr-423 in response to a conformation change, triggered by interaction with GTP-bound CDC42 or RAC1. Activated by phosphorylation at Thr-423 by BRSK2 and by PDPK1. Phosphorylated by JAK2 in response to PRL; this increases PAK1 kinase activity. Phosphorylated at Ser-21 by PKB/AKT; this reduces interaction with NCK1 and association with focal adhesion sites. Upon DNA damage, phosphorylated at Thr-212 and translocates to the nucleoplasm. Phosphorylated at tyrosine residues, which can be enhanced by NTN1.

Disease relevance. Intellectual developmental disorder with macrocephaly, seizures, and speech delay (IDDMSSD) [MIM:618158] An autosomal dominant neurodevelopmental disorder characterized by impaired intellectual development, poor speech, postnatal macrocephaly, and seizures. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, and enables activation by phosphorylation of Thr-423. Phosphorylation of Thr-84 by OXSR1 inhibits activation.

Similarity. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13153-1	1	yes
Q13153-2	2, PAK1B

RefSeq proteins (35): NP_001122092, NP_001363197, NP_001363198, NP_001363199, NP_001363200, NP_001363201, NP_001363202, NP_001363203, NP_001363204, NP_001363205, NP_001363206, NP_001363207, NP_001363208, NP_001363209, NP_001363210, NP_001363211, NP_001363212, NP_001363213, NP_001363214, NP_001363215, NP_001363216, NP_001363217, NP_001363218, NP_001363219, NP_001363220, NP_001363221, NP_001363222, NP_001363223, NP_001363224, NP_001363230, NP_001363231, NP_001363232, NP_001363233, NP_001363234, NP_002567* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000095	CRIB_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR033923	PAK_BD	Domain
IPR036936	CRIB_dom_sf	Homologous_superfamily
IPR051931	PAK3-like	Family

Pfam: PF00069, PF00786

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (96 total): modified residue 24, helix 20, strand 16, mutagenesis site 8, region of interest 5, sequence conflict 4, turn 4, compositionally biased region 3, binding site 3, sequence variant 3, domain 2, initiator methionine 1, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

41 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3FXZ	X-RAY DIFFRACTION	1.64
2QME	X-RAY DIFFRACTION	1.75
9N4U	X-RAY DIFFRACTION	1.77
1YHV	X-RAY DIFFRACTION	1.8
1YHW	X-RAY DIFFRACTION	1.8
8X5Z	X-RAY DIFFRACTION	1.8
3Q52	X-RAY DIFFRACTION	1.8
9D4V	X-RAY DIFFRACTION	1.84
9D4X	X-RAY DIFFRACTION	1.85
9D4Y	X-RAY DIFFRACTION	1.85
9N48	X-RAY DIFFRACTION	1.85
3Q4Z	X-RAY DIFFRACTION	1.89
9D50	X-RAY DIFFRACTION	1.9
5DEW	X-RAY DIFFRACTION	1.9
4ZJI	X-RAY DIFFRACTION	1.99
2HY8	X-RAY DIFFRACTION	2
4DAW	X-RAY DIFFRACTION	2
4EQC	X-RAY DIFFRACTION	2.01
3Q53	X-RAY DIFFRACTION	2.09
5DEY	X-RAY DIFFRACTION	2.1
4ZY6	X-RAY DIFFRACTION	2.15
9NBX	X-RAY DIFFRACTION	2.15
4ZJJ	X-RAY DIFFRACTION	2.2
5DFP	X-RAY DIFFRACTION	2.2
5IME	X-RAY DIFFRACTION	2.22
9D4W	X-RAY DIFFRACTION	2.22
28OQ	X-RAY DIFFRACTION	2.28
6B16	X-RAY DIFFRACTION	2.29
1F3M	X-RAY DIFFRACTION	2.3
3FY0	X-RAY DIFFRACTION	2.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13153-F1	73.90	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 389 (proton acceptor)

Ligand- & substrate-binding residues (3): 276–284; 299; 345–347

Post-translational modifications (24): 2, 21, 57, 84, 115, 131, 142, 144, 149, 153, 174, 185, 199, 201, 204, 212, 219, 220, 223, 225 …

Mutagenesis-validated functional residues (8):

Position	Phenotype
83	abolishes interaction with cdc42, leading to strongly decreased activity; when associated with l-86.
86	abolishes interaction with cdc42, leading to strongly decreased activity; when associated with l-83.
107	abolishes autoinhibition, leading to constitutive kinase activity.
299	strongly decreases activity. abolishes kinase activity; when associated with n-389.
389	abolishes kinase activity; when associated with r-299.
393	abolishes autophosphorylation at thr-423.
423	decreases cdc42-stimulated activity and autophosphorylation.
423	constitutive kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-202433	Generation of second messenger molecules
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-389359	CD28 dependent Vav1 pathway
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-3928664	Ephrin signaling
R-HSA-399954	Sema3A PAK dependent Axon repulsion
R-HSA-428540	Activation of RAC1
R-HSA-445144	Signal transduction by L1
R-HSA-445355	Smooth Muscle Contraction
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-5621575	CD209 (DC-SIGN) signaling
R-HSA-5625740	RHO GTPases activate PKNs
R-HSA-5627117	RHO GTPases Activate ROCKs
R-HSA-5627123	RHO GTPases activate PAKs
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-8964616	G beta:gamma signalling through CDC42
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013407	RHOH GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9013424	RHOV GTPase cycle

MSigDB gene sets: 730 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, ATF_B, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, BIOCARTA_FMLP_PATHWAY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, FREAC2_01, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS

GO Biological Process (40): response to hypoxia (GO:0001666), stimulatory C-type lectin receptor signaling pathway (GO:0002223), chromatin remodeling (GO:0006338), exocytosis (GO:0006887), apoptotic process (GO:0006915), DNA damage response (GO:0006974), positive regulation of cell population proliferation (GO:0008284), cellular response to starvation (GO:0009267), positive regulation of fibroblast migration (GO:0010763), cell migration (GO:0016477), cerebellum development (GO:0021549), establishment of cell polarity (GO:0030010), actin cytoskeleton organization (GO:0030036), positive regulation of cell migration (GO:0030335), cellular response to insulin stimulus (GO:0032869), regulation of actin cytoskeleton organization (GO:0032956), positive regulation of intracellular estrogen receptor signaling pathway (GO:0033148), intracellular signal transduction (GO:0035556), Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096), wound healing (GO:0042060), regulation of MAPK cascade (GO:0043408), positive regulation of axon extension (GO:0045773), positive regulation of insulin receptor signaling pathway (GO:0046628), hepatocyte growth factor receptor signaling pathway (GO:0048012), ephrin receptor signaling pathway (GO:0048013), branching morphogenesis of an epithelial tube (GO:0048754), neuron projection morphogenesis (GO:0048812), regulation of axonogenesis (GO:0050770), positive regulation of stress fiber assembly (GO:0051496), negative regulation of cell proliferation involved in contact inhibition (GO:0060244), negative regulation of cell growth involved in cardiac muscle cell development (GO:0061052), positive regulation of microtubule nucleation (GO:0090063), positive regulation of protein targeting to membrane (GO:0090314), protein localization to cytoplasmic stress granule (GO:1903608), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), positive regulation of vascular associated smooth muscle cell migration (GO:1904754), protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), positive regulation of microtubule polymerization (GO:0031116), regulation of actin filament organization (GO:0110053)

GO Molecular Function (14): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), collagen binding (GO:0005518), ATP binding (GO:0005524), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), gamma-tubulin binding (GO:0043015), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), small GTPase binding (GO:0031267)

GO Cellular Component (23): ruffle (GO:0001726), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), intercalated disc (GO:0014704), Z disc (GO:0030018), lamellipodium (GO:0030027), axon (GO:0030424), dendrite (GO:0030425), nuclear membrane (GO:0031965), ruffle membrane (GO:0032587), protein-containing complex (GO:0032991), nucleus (GO:0005634), cytoskeleton (GO:0005856), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
RHO GTPase Effectors	3
RHO GTPase cycle	3
EPH-Ephrin signaling	2
TCR signaling	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
Fc epsilon receptor (FCERI) signaling	1
Co-stimulation by CD28	1
Semaphorin interactions	1
Signaling by ROBO receptors	1
L1CAM interactions	1
Muscle contraction	1
VEGFA-VEGFR2 Pathway	1
C-type lectin receptors (CLRs)	1
MAPK family signaling cascades	1
G-protein beta:gamma signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cellular response to stress	2
intracellular anatomical structure	2
protein kinase activity	2
cell leading edge	2
plasma membrane bounded cell projection	2
intracellular membraneless organelle	2
neuron projection	2
response to stress	1
response to decreased oxygen levels	1
innate immune response activating cell surface receptor signaling pathway	1
cellular response to lectin	1
chromatin organization	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cellular response to nutrient levels	1
response to starvation	1
fibroblast migration	1
regulation of fibroblast migration	1
positive regulation of cell migration	1
cell motility	1
metencephalon development	1
anatomical structure development	1
establishment or maintenance of cell polarity	1
cytoskeleton organization	1
actin filament-based process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
response to insulin	1
cellular response to peptide hormone stimulus	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1

Protein interactions and networks

STRING

2138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAK1	CDC42	P21181	994
PAK1	AKT1	P31749	981
PAK1	NCK1	P16333	919
PAK1	SLCO6A1	Q86UG4	791
PAK1	GRB2	P29354	775
PAK1	GIT1	Q9Y2X7	721
PAK1	ARHGEF6	Q15052	670
PAK1	GIT2	Q14161	650
PAK1	NF2	P35240	612
PAK1	RABIF	P47224	602
PAK1	RAC1	P15154	580
PAK1	ARPC1B	O15143	578
PAK1	CFL1	P23528	567
PAK1	LIMK1	P53667	556
PAK1	CFL2	Q9Y281	556

IntAct

280 interactions, top by confidence:

A	B	Type	Score
PAK1	RAC1	psi-mi:“MI:0914”(association)	0.980
PAK1	RAC1	psi-mi:“MI:0915”(physical association)	0.980
RAC1	PAK1	psi-mi:“MI:0915”(physical association)	0.980
PAK1	RAC1	psi-mi:“MI:0407”(direct interaction)	0.980
PAK1	CDC42	psi-mi:“MI:0915”(physical association)	0.950
PAK1	ARHGEF7	psi-mi:“MI:2364”(proximity)	0.950
ARHGEF7	PAK1	psi-mi:“MI:0915”(physical association)	0.950
PAK1	ARHGEF7	psi-mi:“MI:0915”(physical association)	0.950
CDC42	PAK1	psi-mi:“MI:0915”(physical association)	0.950
PAK1	CDC42	psi-mi:“MI:0914”(association)	0.950
NCK2	PAK1	psi-mi:“MI:0915”(physical association)	0.940
PAK1	NCK2	psi-mi:“MI:0915”(physical association)	0.940
PAK1	NCK2	psi-mi:“MI:0914”(association)	0.940
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
FBXO28	TRAF5	psi-mi:“MI:0914”(association)	0.740
PAK1	CDK11B	psi-mi:“MI:0915”(physical association)	0.690
PAK1	Rac1	psi-mi:“MI:0915”(physical association)	0.690
PAK1	Cdc42	psi-mi:“MI:0915”(physical association)	0.690

BioGRID (362): NCK2 (Two-hybrid), AKT1 (Reconstituted Complex), PAK1 (Affinity Capture-Western), BRSK1 (Affinity Capture-Western), BRSK1 (Reconstituted Complex), PAK1 (Biochemical Activity), PAK1 (Two-hybrid), PAK1 (Affinity Capture-Western), RAC1 (Reconstituted Complex), GIT1 (Affinity Capture-MS), GIT2 (Affinity Capture-MS), H2AFX (Affinity Capture-MS), PAK1 (Affinity Capture-MS), PAK1 (Affinity Capture-MS), PAK1 (Affinity Capture-MS)

ESM2 similar proteins: A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8XJW8, O00506, O54748, O61125, O75914, O88643, P29678, P31938, P35465, P36583, Q01986, Q02750, Q07192, Q08E52, Q13043, Q13153, Q13177, Q13188, Q17850, Q29502, Q5E9L6, Q5ZJK4, Q61036, Q62829, Q63980, Q64303, Q6IP06, Q6P3Q4, Q6PA14, Q7YQL3, Q7YQL4, Q7ZUQ3, Q802A6

Diamond homologs: A0A7J6K7I9, A0A7J6K7Y0, A0A7J6KD88, A8X775, B1WAR9, C4YRB7, D2HXI8, E1C2I2, E9PSL7, G1X456, G5EGQ3, M3TYT0, O00506, O01583, O01700, O14578, O54874, O61267, O75116, O77819, O80902, O88643, O97627, P05131, P0CY23, P0CY24, P13677, P21146, P25098, P26817, P26818, P32865, P34100, P35465, P38070, P48562, P49025, P49673, P54265, P70335

SIGNOR signaling

119 interactions.

A	Effect	B	Mechanism
PAK1	“down-regulates activity”	CTBP1	phosphorylation
PAK1	down-regulates	STMN1	phosphorylation
PAK1	up-regulates	ARPC1B	phosphorylation
MAPK3	down-regulates	PAK1	phosphorylation
PAK1	down-regulates	WEE1	phosphorylation
PAK1	down-regulates	ARHGDIA	phosphorylation
PAK1	up-regulates	PGM1	phosphorylation
PAK1	unknown	VIM	phosphorylation
PAK1	up-regulates	TBCB	phosphorylation
PAK1	up-regulates	SNAI1	phosphorylation
CRIPAK	up-regulates	PAK1	binding
PAK1	unknown	PXN	phosphorylation
PAK1	up-regulates	ILK	phosphorylation
PAK1	up-regulates	ELF3	phosphorylation
PAK1	down-regulates	NF2	phosphorylation
PAK1	down-regulates	DYNLL1	phosphorylation
PAK1	up-regulates	PA2G4	phosphorylation
PPM1F	down-regulates	PAK1	dephosphorylation
STK11	down-regulates	PAK1	phosphorylation
PAK1	up-regulates	CTTN	phosphorylation
PAK1	up-regulates	CTNNB1	phosphorylation
PAK1	down-regulates	BAD	phosphorylation
PAK1	up-regulates	PLK1	phosphorylation
PAK1	up-regulates	ITGB3BP	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RHOU GTPase cycle	8	34.3×	4e-08
RHOV GTPase cycle	5	22.0×	3e-04
VEGFA-VEGFR2 Pathway	9	19.3×	2e-07
Aggrephagy	5	19.1×	4e-04
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	5	14.9×	1e-03
Regulation of actin dynamics for phagocytic cup formation	5	14.2×	1e-03
Recruitment of mitotic centrosome proteins and complexes	5	10.5×	3e-03
MAPK6/MAPK4 signaling	5	10.5×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
lamellipodium assembly	5	23.8×	7e-04
actin filament organization	8	10.2×	6e-04
cell migration	9	6.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

164 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	21
Uncertain significance	97
Likely benign	16
Benign	6

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1174490	NM_002576.5(PAK1):c.391T>A (p.Tyr131Asn)	Pathogenic
973272	NM_002576.5(PAK1):c.362C>T (p.Pro121Leu)	Pathogenic
1325801	NM_002576.5(PAK1):c.397T>C (p.Ser133Pro)	Likely pathogenic
1325816	NM_002576.5(PAK1):c.328T>A (p.Ser110Thr)	Likely pathogenic
1685392	NM_002576.5(PAK1):c.424T>C (p.Tyr142His)	Likely pathogenic
1700706	NM_002576.5(PAK1):c.1420T>C (p.Tyr474His)	Likely pathogenic
1710273	NM_002576.5(PAK1):c.313C>T (p.Arg105Cys)	Likely pathogenic
2442056	NM_002576.5(PAK1):c.1409T>A (p.Leu470Gln)	Likely pathogenic
2506573	NM_002576.5(PAK1):c.935T>G (p.Ile312Ser)	Likely pathogenic
2506574	NM_002576.5(PAK1):c.1426A>G (p.Ile476Val)	Likely pathogenic
2506575	NM_002576.5(PAK1):c.1111C>T (p.Arg371Cys)	Likely pathogenic
2506576	NM_002576.5(PAK1):c.251C>G (p.Thr84Arg)	Likely pathogenic
2606596	NM_002576.5(PAK1):c.1261C>T (p.Arg421Trp)	Likely pathogenic
3042598	NM_002576.5(PAK1):c.262G>A (p.Gly88Ser)	Likely pathogenic
3061421	NM_002576.5(PAK1):c.427A>G (p.Met143Val)	Likely pathogenic
3382595	NM_002576.5(PAK1):c.850G>A (p.Val284Met)	Likely pathogenic
4277831	NM_002576.5(PAK1):c.1115A>C (p.Glu372Ala)	Likely pathogenic
4687954	NM_002576.5(PAK1):c.209_212del (p.Lys70fs)	Likely pathogenic
587370	NM_002576.5(PAK1):c.392A>G (p.Tyr131Cys)	Likely pathogenic
587371	NM_002576.5(PAK1):c.1286A>G (p.Tyr429Cys)	Likely pathogenic
871651	NM_002576.5(PAK1):c.428T>A (p.Met143Lys)	Likely pathogenic
982892	NM_002576.5(PAK1):c.1409T>G (p.Leu470Arg)	Likely pathogenic
987294	NM_002576.5(PAK1):c.428T>C (p.Met143Thr)	Likely pathogenic

SpliceAI

3015 predictions. Top by Δscore:

Variant	Effect	Δscore
11:77323356:TGATG:T	acceptor_gain	1.0000
11:77332725:GTTAC:G	donor_loss	1.0000
11:77332726:TTAC:T	donor_loss	1.0000
11:77332727:TAC:T	donor_loss	1.0000
11:77332728:A:AG	donor_loss	1.0000
11:77332729:C:CA	donor_loss	1.0000
11:77332866:GCCT:G	acceptor_loss	1.0000
11:77332868:C:CC	acceptor_gain	1.0000
11:77332868:CTGG:C	acceptor_loss	1.0000
11:77332869:T:C	acceptor_loss	1.0000
11:77336078:ACACT:A	donor_loss	1.0000
11:77336079:CACTC:C	donor_loss	1.0000
11:77336080:ACTCA:A	donor_loss	1.0000
11:77336082:TCACT:T	donor_loss	1.0000
11:77336083:CACT:C	donor_loss	1.0000
11:77336084:A:AC	donor_gain	1.0000
11:77336084:AC:A	donor_loss	1.0000
11:77336084:ACT:A	donor_gain	1.0000
11:77336084:ACTCT:A	donor_gain	1.0000
11:77336085:C:A	donor_loss	1.0000
11:77336085:C:CA	donor_gain	1.0000
11:77336085:CT:C	donor_gain	1.0000
11:77336085:CTC:C	donor_gain	1.0000
11:77336085:CTCT:C	donor_gain	1.0000
11:77336085:CTCTC:C	donor_gain	1.0000
11:77336119:C:A	donor_gain	1.0000
11:77336278:GTCAG:G	acceptor_gain	1.0000
11:77336279:TCAG:T	acceptor_gain	1.0000
11:77336280:CAG:C	acceptor_gain	1.0000
11:77336280:CAGC:C	acceptor_gain	1.0000

AlphaMissense

3588 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:77323302:G:T	A537D	1.000
11:77323303:C:G	A537P	1.000
11:77323306:C:G	A536P	1.000
11:77323311:A:T	I534N	1.000
11:77323323:A:G	L530P	1.000
11:77323323:A:T	L530H	1.000
11:77332737:A:G	L515P	1.000
11:77332754:T:A	R509S	1.000
11:77332754:T:G	R509S	1.000
11:77332755:C:A	R509I	1.000
11:77332755:C:G	R509T	1.000
11:77332776:A:G	L502P	1.000
11:77332776:A:T	L502H	1.000
11:77332778:A:C	C501W	1.000
11:77332788:A:G	L498P	1.000
11:77332843:C:A	G480W	1.000
11:77332851:G:T	A477D	1.000
11:77332852:C:G	A477P	1.000
11:77332854:A:C	I476S	1.000
11:77332854:A:T	I476N	1.000
11:77332857:A:G	L475P	1.000
11:77332861:A:C	Y474D	1.000
11:77332863:A:C	L473W	1.000
11:77332863:A:G	L473S	1.000
11:77332866:G:T	A472D	1.000
11:77336090:A:G	L470P	1.000
11:77336105:A:G	L465P	1.000
11:77336105:A:T	L465H	1.000
11:77336109:A:C	Y464D	1.000
11:77336109:A:G	Y464H	1.000

dbSNP variants (sampled 300 via entrez): RS1000004432 (11:77353796 T>C), RS1000013905 (11:77500914 C>T), RS1000017096 (11:77360167 C>T), RS1000022794 (11:77401683 C>G), RS1000033842 (11:77508650 A>G), RS1000036254 (11:77405943 G>C), RS1000041235 (11:77382875 G>A), RS1000093062 (11:77414402 T>C), RS1000102157 (11:77451375 C>A), RS1000104444 (11:77404693 G>A), RS1000121872 (11:77327387 A>C,G), RS1000122717 (11:77386521 C>T), RS1000177687 (11:77338548 T>C), RS1000189568 (11:77492589 C>G), RS1000199737 (11:77474510 T>C)

Disease associations

OMIM: gene MIM:602590 | disease phenotypes: MIM:618158, MIM:181500, MIM:618718

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with macrocephaly, seizures, and speech delay	Strong	Autosomal dominant

Mondo (4): intellectual developmental disorder with macrocephaly, seizures, and speech delay (MONDO:0032568), schizophrenia (MONDO:0005090), neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia (MONDO:0032878), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0100753	Schizophrenia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003264_850	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST007277_15	Tourette syndrome	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL3885636 (PROTEIN FAMILY), CHEMBL3885637 (PROTEIN FAMILY), CHEMBL4296113 (PROTEIN COMPLEX), CHEMBL4600 (SINGLE PROTEIN), CHEMBL5291682 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195510 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

23 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 253,674 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL180022	NERATINIB	4	9,404
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL469	KETOROLAC	4	53,920
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL140	CURCUMIN	3	93,882
CHEMBL165	RESVERATROL	3	60,144
CHEMBL603469	LESTAURTINIB	3
CHEMBL1967878	CENISERTIB	2	358
CHEMBL1980297	ILORASERTIB	2	581
CHEMBL1980715	LAUROGUADINE	2	294
CHEMBL2105734	SEPANTRONIUM BROMIDE	2	366
CHEMBL215152	DEFOSBARASERTIB	2	372
CHEMBL4297467	PADNARSERTIB	2	127
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL607707	PELITINIB	2	6,340
CHEMBL1084546	PF-00562271	1	399
CHEMBL1908397	KW-2449	1	622
CHEMBL1980391	RG-1530	1	37
CHEMBL259084	MLN-8054	1
CHEMBL3128043	PF-03758309	1
CHEMBL494089	GSK-690693	1

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — PAKA subfamily

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
RKI-1447	Inhibition	9.0	pIC50
compound 3 [PMID: 26191365]	Negative	8.15	pKd
FRAX597	Inhibition	8.1	pIC50
FRAX486	Inhibition	8.08	pIC50
PF-3758309	Inhibition	7.44	pKi
Il-94	Inhibition	7.43	pKi
compound 1 [PMID: 20005102]	Inhibition	7.3	pIC50
BJG-05-039	Negative	6.63	pIC50
IPA-3	Inhibition	5.6	pIC50
compound 4 [PMID: 24432870]	Inhibition	5.35	pKi

Binding affinities (BindingDB)

8 measured of 8 human assays (8 total across all organisms); most potent 8 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 nM
FRAX597	IC50	7.7 nM
FRAX414	IC50	20 nM
PKC-412	KD	190 nM
8-Cyclopentyl-2-[4-(4-methylpiperazin-1-yl)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one	IC50	483 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
(E)-N-[4-(3-chloro-4-fluoro-anilino)-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)but-2-enamide	KD	3500 nM
2-methylsulfanyl-6-[4-[3-[3-(trifluoromethyl)anilino]-1H-1,2,4-triazol-5-yl]phenoxy]pyrimidin-4-amine	KD	7500 nM	US-9260417: Therapeutic methods and compositions involving allosteric kinase inhibition

ChEMBL bioactivities

574 potent at pChembl≥5 of 623 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.67	IC50	0.212	nM	STAUROSPORINE
9.55	Kd	0.28	nM	CHEMBL3923175
9.52	IC50	0.3	nM	STAUROSPORINE
9.48	IC50	0.33	nM	CHEMBL3923175
9.46	IC50	0.35	nM	CHEMBL3950903
9.36	IC50	0.437	nM	STAUROSPORINE
9.35	IC50	0.45	nM	CHEMBL3896232
9.27	IC50	0.541	nM	STAUROSPORINE
9.27	IC50	0.54	nM	CHEMBL5091324
9.24	IC50	0.58	nM	CHEMBL3964858
9.24	Kd	0.57	nM	STAUROSPORINE
9.02	Ki	0.95	nM	CHEMBL3818265
9.00	IC50	1	nM	CHEMBL3597011
8.82	IC50	1.5	nM	CHEMBL3914181
8.72	Ki	1.9	nM	CHEMBL3769478
8.72	Ki	1.9	nM	CHEMBL3770909
8.70	Kd	2	nM	STAUROSPORINE
8.70	IC50	2	nM	CHEMBL3942173
8.68	Ki	2.1	nM	CHEMBL3770588
8.68	IC50	2.1	nM	CHEMBL3924245
8.62	IC50	2.4	nM	CHEMBL3770186
8.57	Ki	2.7	nM	CHEMBL3817856
8.55	IC50	2.8	nM	CHEMBL3597013
8.55	IC50	2.8	nM	CHEMBL3933198
8.55	IC50	2.8	nM	CHEMBL3609327
8.52	IC50	3	nM	CHEMBL3596921
8.52	IC50	3	nM	CHEMBL3910608
8.48	Ki	3.3	nM	CHEMBL3818046
8.46	Ki	3.5	nM	CHEMBL3819356
8.43	Ki	3.7	nM	CHEMBL3770443
8.40	Ki	4	nM	CHEMBL3580975
8.40	Ki	4	nM	CHEMBL3824224
8.38	Ki	4.2	nM	CHEMBL2386717
8.37	Ki	4.3	nM	CHEMBL3770363
8.36	Ki	4.4	nM	CHEMBL3818828
8.35	IC50	4.5	nM	CHEMBL3596932
8.34	Ki	4.6	nM	CHEMBL3818592
8.30	Ki	5	nM	CHEMBL3580976
8.30	Ki	5	nM	CHEMBL3580974
8.30	Ki	5	nM	CHEMBL3580975
8.30	Ki	5	nM	CHEMBL3823612
8.30	Ki	5.012	nM	CHEMBL1980995
8.29	Ki	5.13	nM	CHEMBL2386718
8.28	IC50	5.2	nM	CHEMBL3609372
8.28	Ki	5.2	nM	CHEMBL3818479
8.24	IC50	5.8	nM	CHEMBL3596930
8.23	Ki	5.9	nM	CHEMBL3818016
8.22	Ki	6	nM	CHEMBL3769748
8.22	Ki	6	nM	CHEMBL3823523
8.22	IC50	6	nM	CHEMBL3609372

PubChem BioAssay actives

405 with measured affinity, of 1024 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-8-ethyl-2-[2-(1-methylpiperidin-4-yl)ethylamino]pyrido[2,3-d]pyrimidin-7-one	1704344: Inhibition of full length recombinant human N-terminal GST/His6-tagged PAK1 expressed in sf9 insect cells using tetra LRRWSLG as substrate preincubated for 20 min followed by [gamma33P]ATP addition and measured after 120 mins by Hotspot assay	ki	<0.0001	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715233: Inhibition of human PAK1 using RRRLSFAEPG as substrate by [gamma-33P]-ATP assay	ic50	0.0002	uM
2-[[N-[2-[3-ethylsulfonyl-4-(4-methylpiperazin-1-yl)anilino]-5-fluoropyrimidin-4-yl]-5-(hydroxymethyl)-2-methylanilino]methyl]benzonitrile	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0003	uM
[3-[[2-[3-ethylsulfonyl-4-(4-methylpiperazin-1-yl)anilino]-5-fluoropyrimidin-4-yl]-[(2-fluorophenyl)methyl]amino]-4-methylphenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0003	uM
[5-[[2-[3-ethylsulfonyl-4-(4-methylpiperazin-1-yl)anilino]-5-fluoropyrimidin-4-yl]-methylamino]-2,4-dimethylphenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0004	uM
[5-[[2-[3-ethylsulfonyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]anilino]-5-fluoropyrimidin-4-yl]-methylamino]-2,4-dimethylphenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0006	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-[2-(3-fluoro-1-methylazetidin-3-yl)ethyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0009	uM
1-[(3-hydroxyphenyl)methyl]-3-(4-pyridin-4-yl-1,3-thiazol-2-yl)urea;methanesulfonic acid	1119792: Inhibition of PAK1 (unknown origin)	ic50	0.0010	uM
[3-[benzyl-[2-[3-ethylsulfonyl-4-(4-methylpiperazin-1-yl)anilino]-5-fluoropyrimidin-4-yl]amino]-4-methylphenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0015	uM
6-[2-chloro-4-(6-methyl-2-pyridinyl)phenyl]-2-(methylamino)-8-[[5-(methylamino)-1,3-dioxan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0019	uM
8-[(4-aminocyclohexyl)methyl]-6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0019	uM
[3-[ethyl-[2-[3-ethylsulfonyl-4-(4-methylpiperazin-1-yl)anilino]-5-fluoropyrimidin-4-yl]amino]-4-methylphenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0020	uM
[3-[[2-[3-ethylsulfonyl-4-(4-methylpiperazin-1-yl)anilino]-5-fluoropyrimidin-4-yl]-methylamino]-4-methylphenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0021	uM
8-[(4-aminocyclohexyl)methyl]-6-[2-chloro-4-(6-methyl-2-pyridinyl)phenyl]-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0021	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-[(3,3-difluoropiperidin-4-yl)methyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0027	uM
[5-[[2-(3-ethylsulfonyl-5-morpholin-4-ylanilino)-5-fluoropyrimidin-4-yl]-methylamino]-2,4-dimethylphenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0028	uM
6-[2-chloro-4-(1,3-thiazol-5-yl)phenyl]-8-ethyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0028	uM
[5-[[5-fluoro-2-(3-methylsulfonyl-5-morpholin-4-ylanilino)pyrimidin-4-yl]-methylamino]-2,4-dimethylphenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0030	uM
8-(3-aminopropyl)-6-[2-chloro-4-(6-methyl-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0033	uM
8-(3-aminopropyl)-6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0035	uM
8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(6-methyl-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0037	uM
2-N-[(4-chloro-1H-benzimidazol-5-yl)methyl]-4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-methylpyrimidine-2,4-diamine	1229626: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate assessed as substrate phosphorylation at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0040	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(6-fluoro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311585: Inhibition of recombinant human GST-tagged PAK1 kinase domain expressed in baculovirus expression system assessed as suppression of phosphorylation of coumarin/fluorescein-labelled FRET peptide substrate at Ser/Thr19 residues preincubated with substrate for 10 mins followed by enzyme addition measured after 60 mins by Z-Lyte assay	ki	0.0040	uM
2-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-[(6-fluoro-1H-indazol-4-yl)methyl]amino]propan-1-ol	748655: Inhibition of human recombinant GST-tagged PAK1 kinase domain-mediated 5FAM-RRRLSFAEPG phosphorylation expressed in Sf9 cells preincubated for 10 mins prior to substrate addition measured after 30 mins by microfluidic mobility shift assay	ki	0.0042	uM
6-[2-chloro-4-(6-methyl-2-pyridinyl)phenyl]-8-(5,9-dioxa-2-azaspiro[3.5]nonan-7-ylmethyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0043	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-2-(methylamino)-8-[2-(1-methylazetidin-3-yl)oxyethyl]pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0044	uM
8-(3-aminopropyl)-6-[2-chloro-4-(3-methyl-2-oxopyrazin-1-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0046	uM
2-N-[(4-chloro-1H-benzimidazol-5-yl)methyl]-4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-ethylpyrimidine-2,4-diamine	1229626: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate assessed as substrate phosphorylation at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0050	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-pyrrolo[2,3-c]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311585: Inhibition of recombinant human GST-tagged PAK1 kinase domain expressed in baculovirus expression system assessed as suppression of phosphorylation of coumarin/fluorescein-labelled FRET peptide substrate at Ser/Thr19 residues preincubated with substrate for 10 mins followed by enzyme addition measured after 60 mins by Z-Lyte assay	ki	0.0050	uM
2-N-[(4-chloro-1H-benzimidazol-5-yl)methyl]-4-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine	1229626: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate assessed as substrate phosphorylation at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0050	uM
2-N-[(1S)-1-(3H-benzimidazol-5-yl)ethyl]-4-N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]pyrimidine-2,4-diamine	748655: Inhibition of human recombinant GST-tagged PAK1 kinase domain-mediated 5FAM-RRRLSFAEPG phosphorylation expressed in Sf9 cells preincubated for 10 mins prior to substrate addition measured after 30 mins by microfluidic mobility shift assay	ki	0.0051	uM
6-[2-chloro-4-(3-methyl-2-oxopyrazin-1-yl)phenyl]-8-[(3,3-difluoropiperidin-4-yl)methyl]-2-(oxetan-3-ylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0052	uM
(3S)-3-[[8-chloro-11-(2,2-difluoroethyl)-3-fluoro-5H-benzo[b][1,4]benzodiazepin-6-ylidene]amino]-N-propan-2-ylpyrrolidine-1-carboxamide	1242435: Inhibition of wild type dephosphorylated form of PAK1 (249 to 545) (unknown origin) expressed in Escherichia coli using 5-Fluo-Ahx-AKRRRLSSLRA-COOH as substrate preincubated for 60 mins followed by substrate addition measured after 60 mins by Caliper assay	ic50	0.0052	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-(2-methoxyethyl)-2-(oxetan-3-ylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0059	uM
2-N-[(1S)-1-(3-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]-4-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine	1311585: Inhibition of recombinant human GST-tagged PAK1 kinase domain expressed in baculovirus expression system assessed as suppression of phosphorylation of coumarin/fluorescein-labelled FRET peptide substrate at Ser/Thr19 residues preincubated with substrate for 10 mins followed by enzyme addition measured after 60 mins by Z-Lyte assay	ki	0.0060	uM
6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)-8-(piperidin-4-ylmethyl)pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0060	uM
8-(4-aminobutyl)-6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0061	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-ethyl-2-(oxetan-3-ylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0063	uM
8-(3-aminopropyl)-6-[2-chloro-4-(5-methyl-6-oxopyrimidin-1-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0067	uM
4-N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-indol-5-yl)ethyl]pyrimidine-2,4-diamine	748655: Inhibition of human recombinant GST-tagged PAK1 kinase domain-mediated 5FAM-RRRLSFAEPG phosphorylation expressed in Sf9 cells preincubated for 10 mins prior to substrate addition measured after 30 mins by microfluidic mobility shift assay	ki	0.0067	uM
8-[(4-aminocyclohexyl)methyl]-6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0074	uM
6-[2-chloro-4-(6-methyl-2-pyridinyl)phenyl]-8-[[(4S)-3,3-difluoropiperidin-4-yl]methyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0079	uM
8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-one	1280633: Inhibition of human recombinant PAK1 kinase domain using coumarin/fluorescein-labeled FRET peptide as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by Z-LYTE assay	ki	0.0080	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-ethyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0080	uM
6-[2-chloro-4-(1,3-thiazol-5-yl)phenyl]-8-ethyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one;hydrochloride	2152560: Inhibition of TEV protease fused 6His-tagged PAK1 KD (249 to 545 residues) (unknown origin) expressed in Sf21 cells by Z-LYTE biochemical assay	ic50	0.0080	uM
6-(2,4-dichlorophenyl)-8-ethyl-2-(3-fluoro-4-piperazin-1-ylanilino)pyrido[2,3-d]pyrimidin-7-one	1242475: Inhibition of full length PAK1 (unknown origin) by Z’-LYTE assay	ic50	0.0083	uM
[3-[[5-fluoro-2-[4-(4-methylpiperazin-1-yl)-3-methylsulfonylanilino]pyrimidin-4-yl]-methylamino]-4-methylphenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0087	uM
8-(3-amino-2,2-difluoropropyl)-6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308773: Inhibition of human recombinant N-terminal 6-His-tagged PAK1 kinase domain (249 to 545 residues) expressed in Escherichia coli BL21(DE3) assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0090	uM
[4-chloro-3-[[5-fluoro-2-(3-methylsulfonyl-5-morpholin-4-ylanilino)pyrimidin-4-yl]-methylamino]phenyl]methanol	1326054: Inhibition of PAK1 (unknown origin) by ATP-kinaseGlo assay	ic50	0.0096	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-N-(pyridin-4-ylmethyl)-1H-indazole-3-carboxamide	1704344: Inhibition of full length recombinant human N-terminal GST/His6-tagged PAK1 expressed in sf9 insect cells using tetra LRRWSLG as substrate preincubated for 20 min followed by [gamma33P]ATP addition and measured after 120 mins by Hotspot assay	ic50	0.0098	uM

CTD chemical–gene interactions

58 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, increases methylation	7
Resveratrol	affects cotreatment, increases expression, decreases activity, decreases expression, increases phosphorylation	3
bisphenol A	decreases expression, increases methylation	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
(+)-JQ1 compound	decreases expression, decreases reaction, increases phosphorylation	2
Estradiol	decreases expression, increases expression, decreases reaction	2
Nickel	decreases expression, increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tretinoin	increases expression	2
OTX015	decreases expression	1
FR900359	affects phosphorylation	1
mivebresib	decreases expression	1
methylmercuric chloride	decreases expression	1
lasiocarpine	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
diallyl disulfide	decreases reaction, decreases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
tebuconazole	decreases expression	1
cyclo(leucyl-prolyl)	decreases expression	1
1-palmitoyl-2-arachidonyl-3-phosphorylcholine	affects localization	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
bisphenol S	increases expression	1
LDN 193189	decreases expression, affects cotreatment	1
NSC 689534	affects binding, decreases expression	1
Sunitinib	decreases expression	1
Axitinib	decreases reaction, increases phosphorylation	1

ChEMBL screening assays

401 unique, capped per target: 394 binding, 5 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3820951	Binding	Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window. — J Med Chem
CHEMBL1963737	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: PAK1	PubChem BioAssay data set
CHEMBL4033373	ADMET	Inhibition of human PAK1 kinase domain using coumarin and fluorescein-labeled ser/thr19 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors. — J Med Chem

Cellosaurus cell lines

9 cell lines: 8 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1ZS	Abcam HeLa PAK1 KO	Cancer cell line	Female
CVCL_B8LW	Abcam HCT 116 PAK1 KO	Cancer cell line	Male
CVCL_B8ZT	Abcam MCF-7 PAK1 KO	Cancer cell line	Female
CVCL_B9P2	Abcam A-549 PAK1 KO	Cancer cell line	Male
CVCL_D7WF	Ubigene A-549 PAK1 KO	Cancer cell line	Male
CVCL_D9M6	Ubigene HEK293 PAK1 KO	Transformed cell line	Female
CVCL_TB87	HAP1 PAK1 (-) 1	Cancer cell line	Male
CVCL_TB88	HAP1 PAK1 (-) 2	Cancer cell line	Male
CVCL_TB89	HAP1 PAK1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety