PAK3

Summary

PAK3 (p21 (RAC1) activated kinase 3, HGNC:8592) is a protein-coding gene on chromosome Xq23, encoding Serine/threonine-protein kinase PAK 3 (O75914). Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a serine-threonine kinase and forms an activated complex with GTP-bound RAS-like (P21), CDC2 and RAC1. This protein may be necessary for dendritic development and for the rapid cytoskeletal reorganization in dendritic spines associated with synaptic plasticity. Defects in this gene are the cause of a non-syndromic form of X-linked intellectual disability. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 5063 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked syndromic intellectual disability (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 293 total — 8 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002578

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8592
Approved symbol	PAK3
Name	p21 (RAC1) activated kinase 3
Location	Xq23
Locus type	gene with protein product
Status	Approved
Aliases	hPAK3, bPAK
Ensembl gene	ENSG00000077264
Ensembl biotype	protein_coding
OMIM	300142
Entrez	5063

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 26 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000262836, ENST00000360648, ENST00000372007, ENST00000372010, ENST00000417227, ENST00000425146, ENST00000446737, ENST00000484442, ENST00000487802, ENST00000518291, ENST00000519681, ENST00000893580, ENST00000893581, ENST00000893582, ENST00000893583, ENST00000893584, ENST00000893585, ENST00000893586, ENST00000893587, ENST00000893588, ENST00000893589, ENST00000893590, ENST00000935671, ENST00000935672, ENST00000946499, ENST00000946500, ENST00000946501, ENST00000946502

RefSeq mRNA: 16 — MANE Select: NM_002578 NM_001128166, NM_001128167, NM_001128168, NM_001128172, NM_001128173, NM_001324325, NM_001324326, NM_001324327, NM_001324328, NM_001324329, NM_001324330, NM_001324331, NM_001324332, NM_001324333, NM_001324334, NM_002578

CCDS: CCDS14554, CCDS48151, CCDS48152, CCDS48153

Canonical transcript exons

ENST00000372007 — 18 exons

Exon	Start	End
ENSE00000674885	111195842	111195941
ENSE00000830366	111162915	111163046
ENSE00000830368	111163562	111163727
ENSE00000830369	111192127	111192175
ENSE00000830371	111194301	111194418
ENSE00001033913	111152410	111152447
ENSE00001409473	111103159	111103306
ENSE00001428768	111097575	111097684
ENSE00001432080	111097390	111097456
ENSE00001616487	111216421	111216558
ENSE00001626444	111196444	111196640
ENSE00001650298	111192506	111192618
ENSE00001659738	111173018	111173081
ENSE00001677964	111142096	111142196
ENSE00001829749	111096191	111096415
ENSE00002295121	111123077	111123278
ENSE00003656875	111147737	111147890
ENSE00003709774	111220358	111227361

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 99.26.

FANTOM5 (CAGE): breadth broad, TPM avg 11.3475 / max 631.5590, expressed in 889 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197278	7.3933	850
197271	1.7744	279
197279	0.4322	188
197272	0.3512	152
197277	0.2066	95
197269	0.2060	102
197275	0.1776	76
197276	0.1742	98
197270	0.1658	79
197273	0.1562	74

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.10	gold quality
endothelial cell	CL:0000115	98.10	gold quality
entorhinal cortex	UBERON:0002728	97.40	gold quality
orbitofrontal cortex	UBERON:0004167	97.08	gold quality
postcentral gyrus	UBERON:0002581	96.86	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.83	gold quality
parietal lobe	UBERON:0001872	96.39	gold quality
superior frontal gyrus	UBERON:0002661	96.25	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.92	gold quality
CA1 field of hippocampus	UBERON:0003881	94.56	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.52	gold quality
buccal mucosa cell	CL:0002336	94.47	gold quality
substantia nigra pars compacta	UBERON:0001965	93.93	gold quality
superior vestibular nucleus	UBERON:0007227	93.62	gold quality
islet of Langerhans	UBERON:0000006	92.87	gold quality
pons	UBERON:0000988	92.56	gold quality
body of pancreas	UBERON:0001150	92.55	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.92	gold quality
ventral tegmental area	UBERON:0002691	91.65	gold quality
pancreas	UBERON:0001264	91.25	gold quality
occipital lobe	UBERON:0002021	90.77	gold quality
cortical plate	UBERON:0005343	90.74	gold quality
primary visual cortex	UBERON:0002436	90.51	gold quality
medulla oblongata	UBERON:0001896	89.87	gold quality
inferior olivary complex	UBERON:0002127	89.79	gold quality
sural nerve	UBERON:0015488	89.73	gold quality
lateral globus pallidus	UBERON:0002476	88.41	gold quality
ganglionic eminence	UBERON:0004023	88.33	gold quality
prefrontal cortex	UBERON:0000451	87.53	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	66.24
E-ANND-3	yes	21.03
E-HCAD-5	yes	15.35
E-HCAD-25	yes	9.32

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, JUN

miRNA regulators (miRDB)

297 targeting PAK3, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 27)

• PAK3 codes for a splice variant that contains a 45-bp alternatively spliced exon. The exon encodes 15 aa that are inserted in the regulatory domain. PAK3b displays a high kinase activity in starved cells that is not further stimulated by active GTPases. (PMID:12464619)
• PAK3 is a key regulator of synapse formation and plasticity in the hippocampus. The MRX30 mutation might contribute to the cognitive deficits underlying this form of X-linked mental retardation. (PMID:15574732)
• PAK3 mutations result in a specific form of X-linked mental retardation with fairly constant clinical features. (PMID:18523455)
• potential role of PAK3 in the progression of ACTH-producing thymic carcinoid (PMID:20960100)
• p21-Activated kinase 3 (PAK3) protein regulates synaptic transmission through its interaction with the Nck2/Grb4 protein adaptor. (PMID:21949127)
• Group I p21-activated kinases augment Tax-mediated transcriptional activation of human T-cell leukemia virus type 1 long terminal repeats in a kinase-independent manner. (PMID:23622267)
• Results show elevated PAK3 expression at both the mRNA and protein level in cJun/AP-1-over-expressing Rat1a fibroblasts, as well as in transformed human fibroblasts. (PMID:23818969)
• Cdc42Hs binds to the effector domain of PAK3 (PMID:25109462)
• Data show that group I p21-activated kinases (Paks) Pak1 and Pak2 were much more abundant than Pak3 in meningioma. (PMID:25596744)
• This study identified predicted pathogenic, hemizygous variants on chromosome X in disease genes PAK3. (PMID:25666757)
• This study showed that PARK3 messenger RNA levels was significantly upregulated in subjects with schizophrenia in laminar and cellular samples. (PMID:25981171)
• Abnormalities in the PAK1 and PAK3 mRNA levels as well as their altered coexpression patterns were observed in the postmortem brain of subjects with depression. Dysregulated PAK1/PAK3 dependent signaling may be a key factor responsible for volumetric abnormalities observed in the hippocampus and in the prefrontal cortex in depression resulting in altered connectivity of these regions. (PMID:27474226)
• Authors have identified mutations in PAK3, CASK, and MECP2 that likely contribute to intellectual disability, and the findings extend the spectrum of mutations and phenotypes associated with X-linked intellectual disability. (PMID:28481730)
• The miR-193b-3p/PAK3 axis might be a potential novel therapeutic target for OC. (PMID:29169729)
• Determined the crystal structure of the PAK3 catalytic domain and by small angle X-ray scattering, the solution-phase structures of full-length inactive PAK1 and PAK3. The structures reveal a compact but elongated molecular shape. (PMID:30858169)
• Prognostic significance of PAK family kinases in acute myeloid leukemia. (PMID:30890765)
• PAK3 regulates the Akt-GSK3beta-beta-catenin signaling by acting as Ser(473)-Akt kinase in several pancreatic cancer cell lines, promoting cancer stem cell phenotypes. (PMID:31051214)
• Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease. (PMID:31410926)
• Further delineation of the phenotype of PAK3-associated x-linked intellectual disability: Identification of a novel missense mutation and review of literature. (PMID:31678216)
• PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration. (PMID:31843706)
• Integration of hepatitis B virus DNA into p21-activated kinase 3 (PAK3) gene in HepG2.2.15 cells. (PMID:31897927)
• The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis. (PMID:31943058)
• We diagnosed two male siblings with developmental delays as having a PAK3 likely pathogenic variant. This finding expands the list of PAK3 gene mutations associated with neurodevelopmental disorders and provides further details on its clinical features (PMID:32050918)
• Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation. (PMID:34381046)
• PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth. (PMID:34550532)
• Porocarcinomas with PAK1/2/3 fusions: a series of 12 cases. (PMID:38785043)
• PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy. (PMID:39137120)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pak3	ENSMUSG00000031284
rattus_norvegicus	Pak3	ENSRNOG00000004676
drosophila_melanogaster	Pak	FBGN0267698

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), 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), PAK1 (ENSG00000149269), 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 3 — O75914 (reviewed: O75914)

Alternative names: Beta-PAK, Oligophrenin-3, p21-activated kinase 3

All UniProt accessions (1): O75914

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Plays a role in dendrite spine morphogenesis as well as synapse formation and plasticity. Acts as a downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Additionally, phosphorylates TNNI3/troponin I to modulate calcium sensitivity and relaxation kinetics of thin myofilaments. May also be involved in early neuronal development. 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).

Subunit / interactions. Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Shows highly specific binding to the SH3 domains of phospholipase C-gamma and of adapter protein NCK. Interacts with the C-terminal of APP. Interacts with ARHGEF6 and ARHGEF7. Interacts with GIT1 and GIT2.

Subcellular location. Cytoplasm.

Tissue specificity. Restricted to the nervous system. Highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus.

Post-translational modifications. Autophosphorylated when activated by CDC42/p21. Neddylated.

Disease relevance. Intellectual developmental disorder, X-linked 30 (XLID30) [MIM:300558] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic intellectual disability presents with associated physical, neurological and/or psychiatric manifestations. 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, enables phosphorylation of Thr-436 and allows the kinase domain to adopt an active structure.

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

Isoforms (4)

UniProt ID	Names	Canonical?
O75914-1	1, PAK3b	yes
O75914-2	2
O75914-3	3, PAK3cb
O75914-4	4, PAK3c

RefSeq proteins (16): NP_001121638, NP_001121639, NP_001121640, NP_001121644, NP_001121645, NP_001311254, NP_001311255, NP_001311256, NP_001311257, NP_001311258, NP_001311259, NP_001311260, NP_001311261, NP_001311262, NP_001311263, NP_002569* (*=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
IPR035063	STK_PAK3	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 (64 total): helix 17, sequence conflict 9, strand 8, region of interest 6, modified residue 5, compositionally biased region 4, splice variant 3, sequence variant 3, turn 3, domain 2, binding site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6FD3	X-RAY DIFFRACTION	1.52

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75914-F1	72.63	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): 402 (proton acceptor)

Ligand- & substrate-binding residues (2): 289–297; 312

Post-translational modifications (5): 2, 50, 154, 186, 436

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-202433	Generation of second messenger molecules
R-HSA-389359	CD28 dependent Vav1 pathway
R-HSA-3928664	Ephrin signaling
R-HSA-399954	Sema3A PAK dependent Axon repulsion
R-HSA-428540	Activation of RAC1
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-5621575	CD209 (DC-SIGN) signaling
R-HSA-5627123	RHO GTPases activate PAKs
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9013420	RHOU GTPase cycle

MSigDB gene sets: 407 (showing top): ATF_B, GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_NEUROGENESIS, BROWNE_HCMV_INFECTION_16HR_UP, GOMF_GTPASE_BINDING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GGAMTNNNNNTCCY_UNKNOWN, CAGCTG_AP4_Q5

GO Biological Process (19): stimulatory C-type lectin receptor signaling pathway (GO:0002223), axonogenesis (GO:0007409), cellular response to starvation (GO:0009267), dendrite development (GO:0016358), cell migration (GO:0016477), regulation of actin filament polymerization (GO:0030833), regulation of actin cytoskeleton organization (GO:0032956), intracellular signal transduction (GO:0035556), regulation of MAPK cascade (GO:0043408), ephrin receptor signaling pathway (GO:0048013), regulation of axonogenesis (GO:0050770), synapse organization (GO:0050808), dendritic spine morphogenesis (GO:0060997), regulation of postsynapse organization (GO:0099175), MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), dendritic spine development (GO:0060996), regulation of actin filament organization (GO:0110053)

GO Molecular Function (13): protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase activity (GO:0004708), ATP binding (GO:0005524), SH3 domain binding (GO:0017124), small GTPase binding (GO:0031267), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
RHO GTPase cycle	4
TCR signaling	1
Co-stimulation by CD28	1
EPH-Ephrin signaling	1
Semaphorin interactions	1
Signaling by ROBO receptors	1
VEGFA-VEGFR2 Pathway	1
C-type lectin receptors (CLRs)	1
RHO GTPase Effectors	1
MAPK family signaling cascades	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neuron projection morphogenesis	2
neuron projection development	2
anatomical structure development	2
intracellular anatomical structure	2
MAPK cascade	2
protein kinase activity	2
cellular anatomical structure	2
innate immune response activating cell surface receptor signaling pathway	1
cellular response to lectin	1
cell morphogenesis involved in neuron differentiation	1
axon development	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
cell motility	1
regulation of actin polymerization or depolymerization	1
actin filament polymerization	1
regulation of protein polymerization	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
signal transduction	1
regulation of intracellular signal transduction	1
cell surface receptor protein tyrosine kinase signaling pathway	1
axonogenesis	1
regulation of neuron projection development	1
regulation of anatomical structure morphogenesis	1
cell junction organization	1
dendrite morphogenesis	1
dendritic spine development	1
dendritic spine organization	1
regulation of synapse organization	1
postsynapse organization	1
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
enzyme-linked receptor protein signaling pathway	1
dendrite development	1
actin filament organization	1
regulation of actin cytoskeleton organization	1

Protein interactions and networks

STRING

1784 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAK3	ARHGEF7	Q14155	936
PAK3	ARHGEF6	Q15052	887
PAK3	CDC42	P21181	870
PAK3	GIT1	Q9Y2X7	800
PAK3	GIT2	Q14161	700
PAK3	RBM28	Q9NW13	518
PAK3	AKT1	P31749	469
PAK3	RABIF	P47224	417
PAK3	CTNND1	O60716	411
PAK3	EXOC8	Q8IYI6	384
PAK3	PAK2	Q13177	381
PAK3	METTL22	Q9BUU2	365
PAK3	KDM3B	Q7LBC6	364
PAK3	FEM1C	Q96JP0	362
PAK3	OPHN1	O60890	360

IntAct

47 interactions, top by confidence:

A	B	Type	Score
PAK1	NCK2	psi-mi:“MI:0914”(association)	0.940
RAMAC	RNMT	psi-mi:“MI:0914”(association)	0.810
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
ARHGEF7	NCK2	psi-mi:“MI:0914”(association)	0.640
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
MSRB2	BLTP3B	psi-mi:“MI:0914”(association)	0.530
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
PAK3	CDC42	psi-mi:“MI:0915”(physical association)	0.510
RAC1	PAK3	psi-mi:“MI:0915”(physical association)	0.470
RAC1	PAK3	psi-mi:“MI:2364”(proximity)	0.470
PAK3	PLK1	psi-mi:“MI:0915”(physical association)	0.400
STK4	EIF3CL	psi-mi:“MI:0914”(association)	0.350
COMMD2	PCBP2	psi-mi:“MI:0914”(association)	0.350
MRPS18C	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
ITGB8	TARS3	psi-mi:“MI:0914”(association)	0.350
MRPL38	METTL15	psi-mi:“MI:0914”(association)	0.350
MRPL52		psi-mi:“MI:0914”(association)	0.350
PTPRN2	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
RASSF8	PAK3	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT2	PAK3	psi-mi:“MI:0914”(association)	0.350
VCP	SHTN1	psi-mi:“MI:0914”(association)	0.350
LPXN	MED14	psi-mi:“MI:0914”(association)	0.350
TMEM154	SMCHD1	psi-mi:“MI:0914”(association)	0.350
MAPT	PITPNM1	psi-mi:“MI:2364”(proximity)	0.270
MAPT		psi-mi:“MI:2364”(proximity)	0.270

BioGRID (39): RAC1 (Affinity Capture-Western), PAK3 (Biochemical Activity), PAK3 (Affinity Capture-MS), PAK3 (Affinity Capture-MS), PAK3 (Affinity Capture-Western), PAK3 (Affinity Capture-RNA), RHOJ (Two-hybrid), PAK3 (Two-hybrid), PAK3 (Reconstituted Complex), PAK3 (Affinity Capture-MS), PAK3 (Affinity Capture-MS), PAK3 (Affinity Capture-MS), PAK3 (Affinity Capture-MS), PAK3 (Affinity Capture-MS), ARHGEF7 (Two-hybrid)

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: A0A8I5ZNK2, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8XJW8, B0LT89, F1LP90, F1NBT0, G5EEN4, G5EFU0, G5EGQ3, H2L099, O00506, O14047, O14305, O23304, O24527, O54748, O61122, O61125, O75011, O75914, O88506, O88643, O95747, O95819, O96013, P08458, P35465, P83510, Q03497, Q08E52, Q0IHQ8, Q12851, Q13043, Q13153

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
PAK3	down-regulates	TNNI3	phosphorylation
PAK3	down-regulates	CALD1	phosphorylation
PAK3	“down-regulates activity”	SORT1	phosphorylation
PAK3	up-regulates	RAF1	phosphorylation
PAK3	unknown	TNNI3	phosphorylation
PAK3	“up-regulates activity”	SYN1	phosphorylation
PAK3	“up-regulates activity”	MYO6	phosphorylation
PAK3	“up-regulates activity”	PAK3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 46 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
RHOV GTPase cycle	5	42.0×	2e-05
RHOU GTPase cycle	5	41.0×	2e-05
VEGFA-VEGFR2 Pathway	5	20.5×	3e-04
RHO GTPase cycle	6	10.6×	8e-04
Signaling by Receptor Tyrosine Kinases	6	9.1×	1e-03
Signaling by Rho GTPases	6	6.0×	8e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	6	5.9×	8e-03
Infectious disease	7	5.1×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell migration	7	9.8×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	20
Uncertain significance	122
Likely benign	32
Benign	33

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
11568	NM_002578.5(PAK3):c.1255C>T (p.Arg419Ter)	Pathogenic
11569	NM_002578.5(PAK3):c.199C>T (p.Arg67Cys)	Pathogenic
11570	NM_002578.5(PAK3):c.1094C>A (p.Ala365Glu)	Pathogenic
11571	NM_002578.5(PAK3):c.1337G>C (p.Trp446Ser)	Pathogenic
1747066	NM_002578.5(PAK3):c.535G>T (p.Glu179Ter)	Pathogenic
3643785	NM_002578.5(PAK3):c.729dup (p.Ser244fs)	Pathogenic
684413	NM_002578.5(PAK3):c.976G>C (p.Val326Leu)	Pathogenic
870778	NM_002578.5(PAK3):c.490_491insGGAG (p.Pro164fs)	Pathogenic
1706590	NM_002578.5(PAK3):c.1182del (p.Leu395fs)	Likely pathogenic
2499617	NM_002578.5(PAK3):c.176-1G>A	Likely pathogenic
2574914	NM_002578.5(PAK3):c.880G>A (p.Val294Met)	Likely pathogenic
3238768	NM_002578.5(PAK3):c.600+1G>C	Likely pathogenic
3251947	NM_002578.5(PAK3):c.276+1G>T	Likely pathogenic
3337432	NM_002578.5(PAK3):c.616del (p.Val206fs)	Likely pathogenic
3384071	NM_002578.5(PAK3):c.1279T>C (p.Tyr427His)	Likely pathogenic
3572972	NM_002578.5(PAK3):c.748G>T (p.Glu250Ter)	Likely pathogenic
3897772	NM_002578.5(PAK3):c.1268T>A (p.Val423Glu)	Likely pathogenic
3906113	NM_002578.5(PAK3):c.795_796delinsTT (p.Lys265_Lys266delinsAsnTer)	Likely pathogenic
3910031	NM_002578.5(PAK3):c.1519C>T (p.Arg507Ter)	Likely pathogenic
452954	NM_002578.5(PAK3):c.1159G>A (p.Asp387Asn)	Likely pathogenic
4813355	NM_002578.5(PAK3):c.766+3G>T	Likely pathogenic
4846883	NM_002578.5(PAK3):c.1110+1G>T	Likely pathogenic
545071	NM_002578.5(PAK3):c.1403T>G (p.Leu468Arg)	Likely pathogenic
590242	NM_002578.5(PAK3):c.276+5G>A	Likely pathogenic
626256	NM_002578.5(PAK3):c.1270G>A (p.Gly424Arg)	Likely pathogenic
633605	NM_002578.5(PAK3):c.1282T>A (p.Trp428Arg)	Likely pathogenic
689610	NM_002578.5(PAK3):c.1112G>A (p.Cys371Tyr)	Likely pathogenic
981057	NM_002578.5(PAK3):c.403C>T (p.Gln135Ter)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3590 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:111142129:T:A	I70N	1.000
X:111142129:T:C	I70T	1.000
X:111142129:T:G	I70S	1.000
X:111142137:C:A	P73T	1.000
X:111142137:C:T	P73S	1.000
X:111142138:C:A	P73H	1.000
X:111142146:T:C	F76L	1.000
X:111142148:T:A	F76L	1.000
X:111142148:T:G	F76L	1.000
X:111142152:C:G	H78D	1.000
X:111142161:C:G	H81D	1.000
X:111142170:T:C	F84L	1.000
X:111142172:T:A	F84L	1.000
X:111142172:T:G	F84L	1.000
X:111147752:T:A	W113R	1.000
X:111147752:T:C	W113R	1.000
X:111147754:G:C	W113C	1.000
X:111147754:G:T	W113C	1.000
X:111147765:T:A	L117H	1.000
X:111147765:T:C	L117P	1.000
X:111147773:T:C	S120P	1.000
X:111147780:T:A	I122K	1.000
X:111147780:T:C	I122T	1.000
X:111147780:T:G	I122R	1.000
X:111147795:A:C	Q127P	1.000
X:111147816:T:A	V134D	1.000
X:111147819:T:C	L135P	1.000
X:111147828:T:A	L138H	1.000
X:111147828:T:C	L138P	1.000
X:111147833:T:C	F140L	1.000

dbSNP variants (sampled 300 via entrez): RS1000010218 (X:111132285 A>G), RS1000031963 (X:110975588 T>G), RS1000039006 (X:111118396 A>C), RS1000066062 (X:111062368 A>G), RS1000079083 (X:110949413 T>A), RS1000099196 (X:110965953 G>A), RS1000111010 (X:111068805 T>C), RS1000115519 (X:111122413 C>T), RS1000115698 (X:111189207 G>A), RS1000118592 (X:111004319 G>A), RS1000131110 (X:111037526 A>T), RS1000146138 (X:110976178 C>T), RS1000152552 (X:110948851 T>A,C), RS1000162219 (X:111037069 C>A,T), RS1000189401 (X:111002285 T>C)

Disease associations

OMIM: gene MIM:300142 | disease phenotypes: MIM:300558, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 30	Definitive	X-linked
corpus callosum, agenesis of	Definitive	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked syndromic intellectual disability	Definitive	XL

Mondo (6): intellectual disability, X-linked 30 (MONDO:0010361), intellectual disability (MONDO:0001071), congenital anomaly of kidney and urinary tract (MONDO:0019719), microcephaly (MONDO:0001149), non-syndromic X-linked intellectual disability (MONDO:0019181), corpus callosum, agenesis of (MONDO:0009022)

Orphanet (3): X-linked non-syndromic intellectual disability (Orphanet:777), Renal or urinary tract malformation (Orphanet:93545), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

HPO	Term
HP:0000252	Microcephaly

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D061085	Agenesis of Corpus Callosum	C10.500.034; C16.131.666.034; C23.300.008
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C566906	Cakut (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2999 (SINGLE PROTEIN), CHEMBL3885637 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 132,985 (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
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL475251	R-406	2	762
CHEMBL558752	RAF-265	2	2,721
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL1908397	KW-2449	1	622
CHEMBL296468	BMS-387032	1	2,075
CHEMBL3128043	PF-03758309	1	233
CHEMBL574738	AST-487	1	451

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 (4 total), top 4:

Ligand	Action	Affinity	Parameter
FRAX597	Inhibition	7.72	pIC50
FRAX486	Inhibition	7.26	pIC50
PF-3758309	Inhibition	7.0	pIC50
compound 4 [PMID: 24432870]	Inhibition	5.0	pIC50

Binding affinities (BindingDB)

9 measured of 9 human assays (9 total across all organisms); most potent 9 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
FRAX597	IC50	7.7 nM
PKC-412	KD	190 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 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
BMS-387072	KD	1800 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM

ChEMBL bioactivities

68 potent at pChembl≥5 of 68 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.63	IC50	0.235	nM	STAUROSPORINE
9.48	IC50	0.328	nM	STAUROSPORINE
9.46	IC50	0.343	nM	STAUROSPORINE
9.30	Kd	0.5	nM	STAUROSPORINE
9.00	IC50	1	nM	CHEMBL4282837
8.15	Kd	7.1	nM	STAUROSPORINE
8.00	IC50	10	nM	CHEMBL3609326
7.80	Kd	16	nM	SUNITINIB
7.71	IC50	19.3	nM	CHEMBL3609327
7.71	IC50	19.3	nM	CHEMBL5661936
7.64	IC50	23	nM	CHEMBL3609327
7.54	Kd	29	nM	TAE-684
7.46	Kd	35	nM	LESTAURTINIB
7.36	Kd	44	nM	CHEMBL5415503
7.29	IC50	51	nM	CHEMBL3824314
7.26	IC50	55.3	nM	CHEMBL3609326
7.24	IC50	57	nM	CHEMBL3824224
7.19	IC50	64.1	nM	CHEMBL2386715
7.17	IC50	68	nM	CHEMBL3823612
7.15	IC50	70.8	nM	CHEMBL2386717
7.14	IC50	72	nM	CHEMBL3824061
7.04	IC50	92	nM	CHEMBL3823614
7.00	IC50	99	nM	PF-03758309
6.99	IC50	103	nM	CHEMBL466397
6.92	IC50	120	nM	CHEMBL3580968
6.88	IC50	133	nM	CHEMBL2386716
6.85	IC50	140	nM	CHEMBL5090394
6.80	IC50	160	nM	CHEMBL3823523
6.75	IC50	180	nM	CHEMBL3824243
6.75	Kd	180	nM	MIDOSTAURIN
6.72	IC50	190	nM	CHEMBL3823258
6.72	Kd	190	nM	SU-014813
6.68	Kd	210	nM	NINTEDANIB
6.62	IC50	240	nM	CHEMBL3823457
6.61	IC50	244	nM	CHEMBL2386718
6.60	IC50	250	nM	CHEMBL3822836
6.57	IC50	270	nM	CHEMBL3823056
6.43	Kd	370	nM	CHEMBL1908395
6.36	IC50	440.6	nM	CHEMBL5619359
6.34	Kd	460	nM	KW-2449
6.16	Kd	690	nM	R-406
6.11	Kd	770	nM	RAF-265
6.11	Kd	770	nM	DOVITINIB
6.09	IC50	810	nM	CHEMBL3823469
5.96	Kd	1100	nM	PHA-665752
5.86	IC50	1372	nM	CHEMBL4780410
5.68	Kd	2100	nM	JNJ-7706621
5.48	Kd	3300	nM	TOZASERTIB
5.48	Kd	3300	nM	MIDOSTAURIN
5.46	Kd	3500	nM	BMS-387032

PubChem BioAssay actives

67 with measured affinity, of 720 total; 48 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
(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	1715230: Inhibition of human PAK3 using RRRLSFAEPG as substrate by [gamma-33P]-ATP assay	ic50	0.0002	uM
(2S,3R,4R,6R)-11,23-dihydroxy-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(13),9,11,14,19,21(26),22,24,27-nonaen-16-one	1424475: Inhibition of GST-tagged PAK3 (unknown origin) expressed in Escherichia coli using peptide PC9 substrate	ic50	0.0010	uM
6-(2,4-dichlorophenyl)-8-ethyl-2-(3-fluoro-4-piperazin-1-ylanilino)pyrido[2,3-d]pyrimidin-7-one	2155039: Inhibition of full length PAK3 (unknown origin) assessed s reduction in substrate phosphorylation using peptide as substrate by FRET based Z-LYTE kinase assay	ic50	0.0100	uM
Sunitinib	435823: Binding constant for full-length PAK3	kd	0.0160	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	1242473: Inhibition of recombinant human PAK3 by Z’-LYTE assay	ic50	0.0193	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	2152563: Inhibition of PAK3 (unknown origin) by Z-LYTE biochemical assay	ic50	0.0193	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624873: Binding constant for PAK3 kinase domain	kd	0.0290	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507658: Binding affinity to PAK3	kd	0.0350	uM
N-[3-[2-[2-ethoxy-4-(4-methylpiperazin-1-yl)anilino]-7-oxo-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-6-yl]phenyl]-3-(trifluoromethyl)benzamide	1988550: Binding affinity to PAK3 (unknown origin) assessed as dissociation constant by KINOME scan assay	kd	0.0440	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0510	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	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0570	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(6-fluoro-1H-indazol-4-yl)methyl]-2-N-(2-methoxyethyl)pyrimidine-2,4-diamine	748652: Inhibition of PAK3-mediated MEK1 phosphorylation at Ser298 in human EBC1 cells after 2 hrs by HTRF assay	ic50	0.0641	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	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0680	uM
2-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-[(6-fluoro-1H-indazol-4-yl)methyl]amino]propan-1-ol	748652: Inhibition of PAK3-mediated MEK1 phosphorylation at Ser298 in human EBC1 cells after 2 hrs by HTRF assay	ic50	0.0708	uM
4-N-[5-[(1R,2S)-2-fluorocyclopropyl]-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0720	uM
4-N-[5-[(1S,2R)-2-fluorocyclopropyl]-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0920	uM
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	1242467: Inhibition of PAK3 (unknown origin)	ic50	0.0990	uM
N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonylpiperazin-1-yl)piperidin-1-yl]anilino]pyrimidin-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-methoxybenzamide	2167082: Inhibition of C-terminal His6-tagged recombinant human full-length PAK3 expressed in baculovirus infected Sf21 cells by filter binding assay	ic50	0.1030	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-indol-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.1200	uM
4-N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-indol-5-yl)ethyl]pyrimidine-2,4-diamine	748652: Inhibition of PAK3-mediated MEK1 phosphorylation at Ser298 in human EBC1 cells after 2 hrs by HTRF assay	ic50	0.1330	uM
8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(3-fluoro-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1895121: Inhibition of human PAK3 by radiometric PanQinase activity assay	ic50	0.1400	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	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.1600	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)propyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.1800	uM
Midostaurin	435823: Binding constant for full-length PAK3	kd	0.1800	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	435823: Binding constant for full-length PAK3	kd	0.1900	uM
2-N-[(1S)-1-(6-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]-4-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.1900	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624873: Binding constant for PAK3 kinase domain	kd	0.2100	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-methyl-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.2400	uM
2-N-[(1S)-1-(3H-benzimidazol-5-yl)ethyl]-4-N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]pyrimidine-2,4-diamine	748652: Inhibition of PAK3-mediated MEK1 phosphorylation at Ser298 in human EBC1 cells after 2 hrs by HTRF assay	ic50	0.2440	uM
4-N-[5-(3,3-difluorocyclobutyl)-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.2500	uM
4-N-[5-[(1S,2S)-2-fluorocyclopropyl]-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.2700	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624873: Binding constant for PAK3 kinase domain	kd	0.3700	uM
6-[2-(cyclopropylamino)-6-(2,4-dichlorophenyl)-7-oxopyrido[2,3-d]pyrimidin-8-yl]-N-hydroxyhexanamide	2128137: Inhibition of PAK3 (unknown origin)	ic50	0.4406	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624873: Binding constant for PAK3 kinase domain	kd	0.4600	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624873: Binding constant for PAK3 kinase domain	kd	0.6900	uM
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine	435823: Binding constant for full-length PAK3	kd	0.7700	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	624873: Binding constant for PAK3 kinase domain	kd	0.7700	uM
4-N-[5-[(1R,2R)-2-fluorocyclopropyl]-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.8100	uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one	624873: Binding constant for PAK3 kinase domain	kd	1.1000	uM
1-[3,5-bis(trifluoromethyl)phenyl]-3-[1-(1H-pyrazolo[5,4-d]pyrimidin-4-yl)piperidin-4-yl]urea	1737261: Inhibition of PAK3 (unknown origin) using lipid substrate measured after 40 mins by ADP-glo kinase assay	ic50	1.3720	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435823: Binding constant for full-length PAK3	kd	2.1000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	435823: Binding constant for full-length PAK3	kd	3.3000	uM
N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]piperidine-4-carboxamide	435823: Binding constant for full-length PAK3	kd	3.5000	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624873: Binding constant for PAK3 kinase domain	kd	4.0000	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624873: Binding constant for PAK3 kinase domain	kd	4.1000	uM
3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione	624873: Binding constant for PAK3 kinase domain	kd	4.3000	uM
Bosutinib	624873: Binding constant for PAK3 kinase domain	kd	5.7000	uM
8-N-(cyclopropylmethyl)-4-N-(2-methylsulfanylphenyl)-2-(4-piperidin-4-ylpiperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine	674655: Inhibition of PAK3 by FRET assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
trichostatin A	affects cotreatment, decreases expression, increases expression	3
sodium arsenite	affects methylation, decreases expression	3
Panobinostat	affects cotreatment, decreases expression	2
Nickel	decreases expression, increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tretinoin	decreases expression, affects cotreatment	2
testosterone undecanoate	affects cotreatment, decreases expression	1
potassium chromate(VI)	decreases expression	1
cupric chloride	decreases expression	1
coumarin	increases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
casticin	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Arsenic Trioxide	affects cotreatment, decreases expression	1
Asbestos	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Cadmium	increases expression	1
Carbamazepine	affects expression	1
Dactinomycin	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Phthalic Acids	decreases methylation	1
Smoke	increases expression	1
Tetrachloroethylene	increases expression	1

ChEMBL screening assays

240 unique, capped per target: 240 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1011922	Binding	Inhibition of PAK3 at 100 nM relative to control	Structural analysis of ARC-type inhibitor (ARC-1034) binding to protein kinase A catalytic subunit and rational design of bisubstrate analogue inhibitors of basophilic protein kinases. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YD38	SNU-2693	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01678105	PHASE2	COMPLETED	A Phase II Study of Dovitinib in Recurrent and/or Metastatic Adenoid Cystic Carcinoma of the Salivary Glands
NCT06066333	PHASE2	RECRUITING	Study of Radiotherapy and Pembrolizumab in People With Adrenocortical Carcinoma
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01898715	PHASE1	COMPLETED	Phase 1 Study of ATR-101 in Subjects With Advanced Adrenocortical Carcinoma
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01262235	PHASE1/PHASE2	COMPLETED	A Dose Finding Study of TKM-080301 Infusion in Neuroendocrine Tumors (NET) and Adrenocortical Carcinoma (ACC) Patients
NCT00170326	Not specified	COMPLETED	Progressive Ventricular Dysfunction Prevention in Pacemaker Patients
NCT01117792	Not specified	COMPLETED	Subcutaneous Implantable Defibrillator (S-ICD) System - CE Clinical Investigation
NCT02267161	Not specified	COMPLETED	Infants With Agenesis of the Corpus Callosum
NCT02826824	Not specified	UNKNOWN	BECOME CHILDREN OF HOLDERS Corpus Callosum Agenesis Screened IN PERIOD Antenatal
NCT05843110	Not specified	UNKNOWN	Decision-making Process of Couples Confronted With Prenatal Diagnosis of an Isolated CCA
NCT06262152	Not specified	UNKNOWN	Sleep Profile of Patients With Septo-optic Dysplasia
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome