PAK4

Summary

PAK4 (p21 (RAC1) activated kinase 4, HGNC:16059) is a protein-coding gene on chromosome 19q13.2, encoding Serine/threonine-protein kinase PAK 4 (O96013). Serine/threonine-protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell adhesion turnover, cell migration, growth, proliferation or cell survival.

PAK proteins, a family of serine/threonine p21-activating kinases, include PAK1, PAK2, PAK3 and PAK4. PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. They serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK4 interacts specifically with the GTP-bound form of Cdc42Hs and weakly activates the JNK family of MAP kinases. PAK4 is a mediator of filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 10298 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 131 total
• Druggable target: yes — 35 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005884

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16059
Approved symbol	PAK4
Name	p21 (RAC1) activated kinase 4
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000130669
Ensembl biotype	protein_coding
OMIM	605451
Entrez	10298

Gene structure

Transcript identifiers

Ensembl transcripts: 71 — 69 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000321944, ENST00000358301, ENST00000360442, ENST00000593480, ENST00000593690, ENST00000597715, ENST00000597766, ENST00000599386, ENST00000599470, ENST00000599657, ENST00000600350, ENST00000602004, ENST00000896091, ENST00000896092, ENST00000896093, ENST00000896094, ENST00000896095, ENST00000896096, ENST00000896097, ENST00000896098, ENST00000896099, ENST00000896100, ENST00000896101, ENST00000896102, ENST00000896103, ENST00000896104, ENST00000896105, ENST00000896106, ENST00000896107, ENST00000896108, ENST00000896109, ENST00000896110, ENST00000896111, ENST00000896112, ENST00000896113, ENST00000896114, ENST00000896115, ENST00000896116, ENST00000896117, ENST00000896118, ENST00000896119, ENST00000896120, ENST00000896121, ENST00000896122, ENST00000896123, ENST00000896124, ENST00000896125, ENST00000896126, ENST00000896127, ENST00000896128, ENST00000896129, ENST00000896130, ENST00000919867, ENST00000919868, ENST00000919869, ENST00000919870, ENST00000919871, ENST00000919872, ENST00000919873, ENST00000919874, ENST00000919875, ENST00000919876, ENST00000919877, ENST00000919878, ENST00000963840, ENST00000963841, ENST00000963842, ENST00000963843, ENST00000963844, ENST00000963845, ENST00000963846

RefSeq mRNA: 6 — MANE Select: NM_005884 NM_001014831, NM_001014832, NM_001014834, NM_001014835, NM_001394501, NM_005884

CCDS: CCDS12528, CCDS33019

Canonical transcript exons

ENST00000360442 — 10 exons

Exon	Start	End
ENSE00000704690	39176590	39176715
ENSE00000882573	39172918	39173376
ENSE00000882575	39174931	39175064
ENSE00001242921	39169532	39169757
ENSE00001510615	39125786	39125919
ENSE00001777324	39173576	39174010
ENSE00003614813	39168230	39168302
ENSE00003693339	39177675	39177809
ENSE00003963237	39178424	39179404
ENSE00003963343	39175312	39175438

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.2531 / max 161.5269, expressed in 1799 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175682	20.9726	1798
175686	2.2805	520

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	97.50	gold quality
olfactory bulb	UBERON:0002264	97.28	gold quality
diaphragm	UBERON:0001103	96.78	silver quality
lower esophagus mucosa	UBERON:0035834	96.33	gold quality
mucosa of transverse colon	UBERON:0004991	94.62	gold quality
right uterine tube	UBERON:0001302	94.44	gold quality
right lung	UBERON:0002167	94.25	gold quality
parotid gland	UBERON:0001831	93.49	gold quality
metanephros cortex	UBERON:0010533	93.32	gold quality
upper lobe of left lung	UBERON:0008952	92.80	gold quality
left ventricle myocardium	UBERON:0006566	92.64	gold quality
adenohypophysis	UBERON:0002196	92.56	gold quality
saliva-secreting gland	UBERON:0001044	92.53	gold quality
nasal cavity epithelium	UBERON:0005384	92.48	gold quality
pituitary gland	UBERON:0000007	92.37	gold quality
skin of leg	UBERON:0001511	92.34	gold quality
upper lobe of lung	UBERON:0008948	92.32	gold quality
minor salivary gland	UBERON:0001830	92.22	gold quality
pancreatic ductal cell	CL:0002079	92.14	gold quality
right testis	UBERON:0004534	92.12	gold quality
adult mammalian kidney	UBERON:0000082	92.09	gold quality
left testis	UBERON:0004533	92.08	gold quality
esophagus mucosa	UBERON:0002469	92.07	gold quality
right lobe of thyroid gland	UBERON:0001119	91.94	gold quality
transverse colon	UBERON:0001157	91.75	gold quality
right ovary	UBERON:0002118	91.60	gold quality
cervix squamous epithelium	UBERON:0006922	91.56	silver quality
skin of abdomen	UBERON:0001416	91.53	gold quality
mouth mucosa	UBERON:0003729	91.49	gold quality
left lobe of thyroid gland	UBERON:0001120	91.48	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YY1

miRNA regulators (miRDB)

87 targeting PAK4, 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-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889

Literature-anchored findings (GeneRIF, showing 40)

• PAK4 interacts with KGF receptor and mediate anti-apoptosis effects of KGF on epithelial cells. (PMID:12529371)
• PAK4 can negatively regulate the activation of Rho through a direct protein-protein interaction with G protein-linked Rho GEFs (PMID:14625312)
• PAK4 mediates morphological changes through regulation of GEF-H1 (PMID:15827085)
• PAK4 has a role in TNF-alpha induced cell survival pathyways by facilitating TRADD binding to the TNF Receptor (PMID:16227624)
• PAK4 and alphaPIX can induce highly localized changes in actin dynamics and thereby regulate size and number of podosomes in primary human macrophages. (PMID:16897755)
• bring novel insights into our understanding of synergistic regulation of MUC5AC mucin by both pathological and physiological inducers (PMID:17555715)
• RNAi-mediated or dominant-negative suppression of Pak4, major regulators of cytoskeletal signaling downstream of Cdc42 or Rac1, markedly inhibits EC lumen and tube formation. (PMID:18319301)
• These results support a model whereby hepatocyte growth factor-stimulated cell migration also requires a cofilin phosphorylation step that is mediated by PAK4. (PMID:18424072)
• human Mbt homologue PAK4 leads to anchorage-independent growth and provide a functional link between a PAK protein and the cadherin-catenin complex. (PMID:18636970)
• pneumolysin selectively induced expression of MKP1 via a TLR4-dependent MyD88-TRAF6-ERK pathway, which inhibited the PAK4-JNK signaling pathway,leading to up-regulation of MUC5AC mucin production (PMID:18782768)
• although the PAK4 gene is not activated by mutation in cell lines with gene amplification, an oncogenic form of the KRAS2 gene is present in these cells and oncogenic KRAS2 can activate PAK4 (PMID:18836286)
• Like RIOK3, PAK4 promotes pancreas ductal cell motility and invasion in pancreatic cancer (PMID:19050074)
• PAK4 overexpression through amplification or other mechanisms promotes the proliferation and/or survival of oral squamous-cell carcinoma cells (PMID:19594544)
• DGCR6L, a novel PAK4 interacting protein, regulated PAK4-mediated migration of human gastric cancer cells via LIMK1. (PMID:19778628)
• regulates prostate cancer cell adhesion (PMID:20406887)
• PAK4 is closely correlated to the progression and metastasis of breast cancer. (PMID:20501374)
• p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration (PMID:20507994)
• Data show that both Pak5 and constitutively active Pak4, the founding member of the Group B Paks, directly phosphorylate p120 in vitro. (PMID:20564219)
• Data show that active PAK4 can affect (cap-independent) translation from specific IRES sequences in vivo, and that the N-terminal domain is critical for this regulation. (PMID:20578242)
• This study demonstrates that controlled regulation of PAK4 is required for apical junction formation in lung epithelial cells and highlights potential cross-talk between two Cdc42 targets, PAK4 and Par6B. (PMID:20631255)
• PAK4 is activated by cell attachment to vitronectin as mediated by PAK4 binding partner integrin alphavbeta5. (PMID:20719960)
• Pak4 overexpression promoted ovarian cancer cell migration and invasion in a c-Src, MEK-1, MMP2, and kinase-dependent manner, and induced cell proliferation through the Pak4/c-Src/EGFR pathway that controls cyclin D1 and CDC25A expression. (PMID:20926745)
• Findings reveal that CDK5RAP3 is widely overexpressed in hepatocellular carcinoma and that overexpression of CDK5RAP3 promotes HCC metastasis through PAK4 activation (PMID:21385901)
• PKD can also regulate LIMK through direct phosphorylation and activation of its upstream kinase p21-activated kinase 4 (PAK4). (PMID:21832093)
• Small-molecule PAK4 kinase inhibitor LCH- 7749944 was identified to be capable of inhibiting PAK4 signaling pathways and suppressing PAK4-mediated gastric cancer cell behaviors including proliferation, migration and invasion. (PMID:22085492)
• PAK4 is required for metaphase spindle positioning and anchoring. (PMID:22450748)
• PAK4 is strongly inhibited by an auto-inhibitory domain formed by amino acids 20 to 68. (PMID:22653441)
• Overexpression of PAK4 harbouring a somatic mutation, E329K, increased the HGF-driven motility of metastatic prostate carcinoma cells. (PMID:22689056)
• PAK4 regulated cAMP-induced neuroendocrine differentiation, which is known to promote tumor progression.in prostate neoplasms (PMID:22710715)
• these findings demonstrate that miR-145 downregulates P-ERK expression by targeting PAK4 and leads to inhibition of tumor growth. (PMID:22766504)
• Full-length PAK4 is constitutively autoinibited, but mutation of the pseudosubstrate releases this inhibition. (PMID:22988085)
• we confirmed that the mechanisms of the Pak4-induced cell cycle arrest invovlve the activation of the ATM/Chk1/2/p53 pathway. (PMID:23229348)
• Results support a role for the PAK4 and PAK1 in the proliferation of mutant KRAS-driven colorectal carcinoma cells via pathways not involving RAF/MEK/ERK and PI3K/AKT signaling. (PMID:23233484)
• Interaction between PAK4 and MMP-2 regulated anoikis, cell migration and invasion in glioma. (PMID:23254288)
• increased expression of Pak4 might lead to the establishment and progression of endometriosis by enhanced cellular viability and invasiveness in endometrial cells. (PMID:23293332)
• PAK4 should be considered a signalling integrator regulating numerous fundamental cellular processes. [Review] (PMID:23642861)
• Genotype TT for rs9676717 in PAK4 gene and no drinking may be predictive of the interferon-a treatment success. (PMID:23652058)
• Pak4 is an important regulator of Endometrial cancer cell migration and invasion (PMID:23790167)
• PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1). (PMID:23841590)
• PAK4-SCG10 signaling occurs in gastric cancer cell invasion. (PMID:23893240)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pak4	ENSDARG00000018110
mus_musculus	Pak4	ENSMUSG00000030602
rattus_norvegicus	Pak4	ENSRNOG00000019883

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), 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 4 — O96013 (reviewed: O96013)

Alternative names: p21-activated kinase 4

All UniProt accessions (5): O96013, M0R0L9, M0R1R1, M0R2X4, M0R3G6

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 adhesion turnover, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN. Promotes kinase-independent stabilization of RHOU, thereby contributing to focal adhesion disassembly during cell migration.

Subunit / interactions. Interacts with FGFR2 and GRB2. Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and weakly with RAC1. Interacts with INKA1. Interacts with SH3RF2. Interacts with RHOU and PAXI; the PAK4-RHOU complex protects RHOU from ubiquitination and acts as a scaffold to support paxillin/PAXI phosphorylation.

Subcellular location. Cytoplasm.

Tissue specificity. Highest expression in prostate, testis and colon.

Post-translational modifications. Autophosphorylated on serine residues when activated by CDC42/p21 (Ref.33). Phosphorylated on tyrosine residues upon stimulation of FGFR2. Methylated by SETD6. Polyubiquitinated, leading to its proteasomal degradation.

Activity regulation. Inhibited by INKA1; which inhibits the serine/threonine-protein kinase activity by binding PAK4 in a substrate-like manner.

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

Isoforms (4)

UniProt ID	Names	Canonical?
O96013-1	1	yes
O96013-2	2
O96013-3	3
O96013-4	4

RefSeq proteins (6): NP_001014831, NP_001014832, NP_001014834, NP_001014835, NP_001381430, NP_005875* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000095	CRIB_dom	Domain
IPR000719	Prot_kinase_dom	Domain
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 (82 total): helix 20, modified residue 13, strand 13, turn 8, mutagenesis site 6, compositionally biased region 5, binding site 4, splice variant 4, region of interest 3, domain 2, sequence variant 2, chain 1, active site 1

Structure

Experimental structures (PDB)

49 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2J0I	X-RAY DIFFRACTION	1.6
2Q0N	X-RAY DIFFRACTION	1.75
5VEF	X-RAY DIFFRACTION	1.75
5ZJW	X-RAY DIFFRACTION	1.8
5XVA	X-RAY DIFFRACTION	1.85
4JDI	X-RAY DIFFRACTION	1.85
8AHG	X-RAY DIFFRACTION	1.89
6WLY	X-RAY DIFFRACTION	1.9
7S48	X-RAY DIFFRACTION	1.9
4FIH	X-RAY DIFFRACTION	1.97
4FII	X-RAY DIFFRACTION	2
4JDH	X-RAY DIFFRACTION	2
7S47	X-RAY DIFFRACTION	2
8AHH	X-RAY DIFFRACTION	2.04
4XBU	X-RAY DIFFRACTION	2.06
2OV2	X-RAY DIFFRACTION	2.1
2X4Z	X-RAY DIFFRACTION	2.1
5XVG	X-RAY DIFFRACTION	2.1
7S46	X-RAY DIFFRACTION	2.1
4APP	X-RAY DIFFRACTION	2.2
4O0Y	X-RAY DIFFRACTION	2.2
6WLX	X-RAY DIFFRACTION	2.2
2BVA	X-RAY DIFFRACTION	2.3
2CDZ	X-RAY DIFFRACTION	2.3
4FIJ	X-RAY DIFFRACTION	2.3
4JDJ	X-RAY DIFFRACTION	2.3
5VED	X-RAY DIFFRACTION	2.3
4JDK	X-RAY DIFFRACTION	2.4
5UPK	X-RAY DIFFRACTION	2.4
9D52	X-RAY DIFFRACTION	2.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O96013-F1	71.26	0.45

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): 440 (proton acceptor)

Ligand- & substrate-binding residues (4): 327–335; 350; 396–398; 458–460

Post-translational modifications (13): 41, 78, 104, 148, 167, 181, 187, 195, 207, 258, 267, 291, 474

Mutagenesis-validated functional residues (6):

Position	Phenotype
19	no change in cell motility; in association with l-22.
22	no change in cell motility; in association with l-19.
350	no change in cell motility; in association with m-351.
351	no change in cell motility; in association with m-350.
445	approximately 30-fold increased autophosphorylation (constitutively active mutant).
474	approximately 3-fold increased autophosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-428540	Activation of RAC1
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-9013408	RHOG 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: 245 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GOBP_DENDRITE_DEVELOPMENT, GOBP_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_GROWTH, GOBP_NEUROGENESIS, HNF1_Q6, SP1_Q2_01, COUP_01, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_CELL_JUNCTION_ORGANIZATION

GO Biological Process (15): regulation of cell growth (GO:0001558), apoptotic process (GO:0006915), cytoskeleton organization (GO:0007010), signal transduction (GO:0007165), cellular response to starvation (GO:0009267), cell migration (GO:0016477), intracellular signal transduction (GO:0035556), regulation of MAPK cascade (GO:0043408), positive regulation of angiogenesis (GO:0045766), protein stabilization (GO:0050821), dendritic spine development (GO:0060996), positive regulation of focal adhesion disassembly (GO:0120183), negative regulation of endothelial cell apoptotic process (GO:2000352), protein phosphorylation (GO:0006468), cell-cell adhesion (GO:0098609)

GO Molecular Function (10): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein-macromolecule adaptor activity (GO:0030674), cadherin binding involved in cell-cell adhesion (GO:0098641), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), adherens junction (GO:0005912), focal adhesion (GO:0005925)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	10
Signaling by ROBO receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
protein kinase activity	2
cellular anatomical structure	2
cytoplasm	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
organelle organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
cell motility	1
signal transduction	1
MAPK cascade	1
regulation of intracellular signal transduction	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
regulation of protein stability	1
dendrite development	1
anatomical structure development	1
focal adhesion disassembly	1
regulation of focal adhesion disassembly	1
positive regulation of cell-substrate junction organization	1
negative regulation of apoptotic process	1
endothelial cell apoptotic process	1
regulation of endothelial cell apoptotic process	1
phosphorylation	1
protein modification process	1
cell adhesion	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1

Protein interactions and networks

STRING

2564 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAK4	CDC42	P21181	947
PAK4	RHOU	Q7L0Q8	854
PAK4	INKA1	Q96EL1	826
PAK4	CFL2	Q9Y281	747
PAK4	CFL1	P23528	744
PAK4	ITGB5	P18084	743
PAK4	PIK3R1	P27986	681
PAK4	ARHGEF2	Q92974	676
PAK4	DGCR6L	Q9BY27	665
PAK4	ARHGEF6	Q15052	631
PAK4	ARHGEF7	Q14155	627
PAK4	LIMK1	P53667	569
PAK4	AKT1	P31749	556
PAK4	SSH1	Q8WYL5	546
PAK4	RABIF	P47224	533

IntAct

134 interactions, top by confidence:

A	B	Type	Score
PAK4	YWHAZ	psi-mi:“MI:0914”(association)	0.920
PAK4	YWHAZ	psi-mi:“MI:0915”(physical association)	0.920
PAK4	YWHAG	psi-mi:“MI:0915”(physical association)	0.910
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
CDC42	PAK4	psi-mi:“MI:0915”(physical association)	0.820
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
PAK4	YWHAE	psi-mi:“MI:0915”(physical association)	0.760
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PAK4	INKA1	psi-mi:“MI:0915”(physical association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
PAK4	SFN	psi-mi:“MI:0915”(physical association)	0.630
WASL	PAK4	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
PAK4	WASL	psi-mi:“MI:0915”(physical association)	0.620
PAK4	WASL	psi-mi:“MI:0403”(colocalization)	0.620
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560

BioGRID (274): PAK6 (Affinity Capture-MS), PAK7 (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), ARHGEF11 (Affinity Capture-MS), SUPT5H (Affinity Capture-MS), GGNBP2 (Affinity Capture-MS), KLHL42 (Affinity Capture-MS), PAK4 (Affinity Capture-MS), PAK4 (Affinity Capture-MS), NAA20 (Co-fractionation), NAA25 (Co-fractionation), PAK4 (Co-fractionation), PAK4 (Co-fractionation), PPM1B (Co-fractionation), PAK4 (Affinity Capture-MS)

ESM2 similar proteins: A0A194VNL2, A4QXX4, B0WAU8, B0XPE4, G4N6Z6, G4N7X0, G5EFU0, G5EGQ3, H2L099, O24527, O42626, O96013, P0C198, P0CP70, P0CP71, P0CS76, P0CS77, P0DP15, P11837, P32490, P32491, P38679, P48479, Q0UY20, Q16W24, Q17850, Q19469, Q23356, Q2GYV9, Q2ULU3, Q2VWQ3, Q4P5N0, Q4WHP3, Q4WJJ0, Q501Q9, Q5B4Z3, Q5BBL3, Q5U4C9, Q754N7, Q75DK7

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

24 interactions.

A	Effect	B	Mechanism
PAK4	unknown	PXN	phosphorylation
PAK4	up-regulates	ITGB5	phosphorylation
PAK4	up-regulates	RAN	phosphorylation
PAK4	unknown	RAN	phosphorylation
PAK4	up-regulates	PAK4	phosphorylation
PAK4	up-regulates	CTNNB1	phosphorylation
PAK4	“down-regulates quantity”	FH	phosphorylation
PAK4	“down-regulates quantity by destabilization”	SMAD2	phosphorylation
PAK4	“down-regulates activity”	ARHGEF2	phosphorylation
PAK4	“up-regulates activity”	ESR1	phosphorylation
PAK4	“up-regulates activity”	CEBPB	phosphorylation
PAK4	“down-regulates activity”	ITGB1BP1	phosphorylation
PAK4	“up-regulates quantity by stabilization”	SNAI2	phosphorylation
PAK4	“down-regulates activity”	STMN1	phosphorylation
PAK4	“up-regulates activity”	PAK4	phosphorylation
PAK4	“down-regulates quantity by destabilization”	NFE2L2	phosphorylation
PAK4	“up-regulates activity”	PACSIN1	phosphorylation
PAK4	“up-regulates activity”	SYNJ1	phosphorylation
PRKD1	“up-regulates activity”	PAK4	phosphorylation
PRKD3	“up-regulates activity”	PAK4	phosphorylation
PAK4	“up-regulates activity”	MZF1	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
Activation of BAD and translocation to mitochondria	7	68.3×	1e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	60.3×	2e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	60.3×	2e-09
Activation of BH3-only proteins	7	44.6×	1e-08
RHO GTPases activate PKNs	7	28.5×	3e-07
Intrinsic Pathway for Apoptosis	7	26.3×	4e-07
FOXO-mediated transcription	5	21.5×	8e-05
Apoptosis	8	17.2×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	24.7×	6e-05
intracellular protein localization	9	10.6×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	109
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1773 predictions. Top by Δscore:

Variant	Effect	Δscore
19:39125916:GCCG:G	donor_gain	1.0000
19:39125920:G:GA	donor_loss	1.0000
19:39125920:G:GG	donor_gain	1.0000
19:39169529:CA:C	acceptor_loss	1.0000
19:39169530:A:AG	acceptor_gain	1.0000
19:39169530:A:AT	acceptor_loss	1.0000
19:39169530:AG:A	acceptor_gain	1.0000
19:39169530:AGGCC:A	acceptor_gain	1.0000
19:39169531:G:GC	acceptor_gain	1.0000
19:39169531:GG:G	acceptor_gain	1.0000
19:39169531:GGC:G	acceptor_gain	1.0000
19:39169531:GGCC:G	acceptor_gain	1.0000
19:39169531:GGCCG:G	acceptor_gain	1.0000
19:39169754:CAAGG:C	donor_loss	1.0000
19:39169756:AGG:A	donor_loss	1.0000
19:39169757:GGT:G	donor_loss	1.0000
19:39169759:T:A	donor_loss	1.0000
19:39174008:GAG:G	donor_gain	1.0000
19:39174011:G:GA	donor_loss	1.0000
19:39174011:G:GG	donor_gain	1.0000
19:39174012:T:G	donor_loss	1.0000
19:39174928:CAGGT:C	acceptor_loss	1.0000
19:39174930:G:GC	acceptor_loss	1.0000
19:39175062:CAGGT:C	donor_loss	1.0000
19:39175065:GT:G	donor_loss	1.0000
19:39175309:CAGGA:C	acceptor_loss	1.0000
19:39175310:A:AG	acceptor_gain	1.0000
19:39175310:AG:A	acceptor_gain	1.0000
19:39175311:G:GT	acceptor_gain	1.0000
19:39175311:GG:G	acceptor_gain	1.0000

AlphaMissense

3791 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:39169602:T:C	F17L	1.000
19:39169604:C:A	F17L	1.000
19:39169604:C:G	F17L	1.000
19:39169668:T:A	W39R	1.000
19:39169668:T:C	W39R	1.000
19:39169669:G:C	W39S	1.000
19:39169670:G:C	W39C	1.000
19:39169670:G:T	W39C	1.000
19:39173822:T:C	F304L	1.000
19:39173823:T:C	F304S	1.000
19:39173824:C:A	F304L	1.000
19:39173824:C:G	F304L	1.000
19:39173835:T:A	L308Q	1.000
19:39173835:T:C	L308P	1.000
19:39173861:C:T	P317S	1.000
19:39173862:C:A	P317H	1.000
19:39173874:T:C	L321P	1.000
19:39173892:T:A	I327N	1.000
19:39173894:G:C	G328R	1.000
19:39173894:G:T	G328C	1.000
19:39173895:G:A	G328D	1.000
19:39173895:G:T	G328V	1.000
19:39173900:G:A	G330S	1.000
19:39173900:G:C	G330R	1.000
19:39173900:G:T	G330C	1.000
19:39173901:G:A	G330D	1.000
19:39173901:G:C	G330A	1.000
19:39173901:G:T	G330V	1.000
19:39173907:C:A	T332K	1.000
19:39173909:G:C	G333R	1.000

dbSNP variants (sampled 300 via entrez): RS1000102121 (19:39173483 T>A,C), RS1000156501 (19:39139261 C>T), RS1000161331 (19:39177481 G>A,C,T), RS1000205428 (19:39158703 A>G), RS1000223813 (19:39138146 T>C), RS1000231553 (19:39127386 T>C), RS1000312308 (19:39169379 G>A,T), RS1000317847 (19:39181355 C>A), RS1000370460 (19:39181202 G>A,T), RS1000427273 (19:39164388 C>G), RS1000464452 (19:39126267 G>C), RS1000481085 (19:39139440 G>A,T), RS1000508268 (19:39160220 T>C), RS1000517759 (19:39126130 G>A,C), RS1000590564 (19:39159184 C>A,G)

Disease associations

OMIM: gene MIM:605451 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): prostate cancer (MONDO:0008315), hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (2): Familial prostate cancer (Orphanet:1331), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4482 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

35 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 152,357 (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
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1231124	AZD-1480	2	1,576
CHEMBL14762	SELICICLIB	2	3,787
CHEMBL1721885	SU-014813	2	363
CHEMBL1922094	APITOLISIB	2	3,070
CHEMBL1967878	CENISERTIB	2	358
CHEMBL1976040	ADAVOSERTIB	2	1,738
CHEMBL2386889	SCH-900776	2	740
CHEMBL3979920	MIVAVOTINIB	2	103
CHEMBL4297467	PADNARSERTIB	2	127
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2
CHEMBL572878	TOZASERTIB	2
CHEMBL574737	UCN-01	2
CHEMBL1084546	PF-00562271	1
CHEMBL1230607	PHA-793887	1
CHEMBL1908397	KW-2449	1
CHEMBL1980391	RG-1530	1
CHEMBL2041933	AZD-7762	1
CHEMBL3128043	PF-03758309	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — PAKB subfamily

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
compound 4 [PMID: 24432870]	Inhibition	8.12	pIC50
GSK690693	Inhibition	8.0	pIC50
PF-3758309	Inhibition	7.82	pKi
AMG28	Inhibition	6.96	pIC50
FRAX486	Inhibition	6.11	pIC50
FRAX597	Inhibition	5.0	pIC50

Binding affinities (BindingDB)

58 measured of 93 human assays (93 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]-N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	EC50	0.94 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(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-carboxylate	KI	1.6 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
Staurosporine	KD	1.7 nM
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-[(2-methylthieno[2,3-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	KI	1.9 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-[(2-cyanopyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	EC50	1.9 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	EC50	2.4 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(9-methylpurin-6-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	EC50	2.5 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[(2-cyanoquinazolin-4-yl)amino]-N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	3 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-N-[(1R,2S)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	3.5 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-[(2-cyanoquinazolin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	KI	3.6 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	EC50	4.4 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-[(6-methylthieno[2,3-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	KI	5.2 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-(thieno[2,3-d]pyrimidin-4-ylamino)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	KI	5.2 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-(thieno[3,2-d]pyrimidin-4-ylamino)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	KI	6.7 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
FRAX597	IC50	7.7 nM
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-[[2-(trifluoromethyl)pyrimidin-4-yl]amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	KI	8.3 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(2S)-2-benzyl-4-methylpiperazin-1-yl]-[3-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]methanone	KI	11 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]-6,6-dimethyl-N-(2-phenylcyclopropyl)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	14 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(6-methylthieno[2,3-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	15 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
6,6-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]-3-(thieno[2,3-d]pyrimidin-4-ylamino)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	16 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[(2-cyanoquinazolin-4-yl)amino]-6,6-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	18 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
6,6-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]-3-(thieno[3,2-d]pyrimidin-4-ylamino)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	18 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
1-(3H-benzimidazol-5-yl)-5-(2,3-difluorophenyl)pyrrolidine-2,4-dione	KI	18.8 nM	US-8530670: Inhibitors
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-(thieno[2,3-d]pyrimidin-4-ylamino)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	EC50	19 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
6,6-dimethyl-3-[(2-methylthieno[2,3-d]pyrimidin-4-yl)amino]-N-[(1R,2S)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	20 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-3-[(5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	EC50	20 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-[(5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	EC50	20 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
FRAX414	IC50	20 nM
6,6-dimethyl-3-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino]-N-[(1R,2S)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	21 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-N-[(1S,2R)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	24 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
6,6-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]-3-[[2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-yl]amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	25 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
6,6-dimethyl-3-[(2-methylquinazolin-4-yl)amino]-N-[(2S)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	34 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[(2-chloroquinazolin-4-yl)amino]-6,6-dimethyl-N-(2-phenylcyclopropyl)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	38 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-[(5-fluoro-2-methoxypyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	KI	39 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[(2-cyanopyrimidin-4-yl)amino]-N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	40 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
6,6-dimethyl-N-[(1S)-2-phenylcyclopropyl]-3-(thieno[3,2-d]pyrimidin-4-ylamino)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	41 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[(2-cyanopyrimidin-4-yl)amino]-6,6-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	47 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[(2-cyclopropylquinazolin-4-yl)amino]-6,6-dimethyl-N-[(2S)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	55 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-(furo[3,2-d]pyrimidin-4-ylamino)-6,6-dimethyl-N-[(1S,2R)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	58 nM	US-8530494: Buprenophine analogs
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-3-(furo[3,2-d]pyrimidin-4-ylamino)-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	58 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylpyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	EC50	67.1 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-[(5-fluoro-6-methylpyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	EC50	69 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[[4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-6-methoxy-1,3,5-triazin-2-yl]amino]-6,6-dimethyl-N-[(2R)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	76 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
6,6-dimethyl-N-[(2R)-2-phenylcyclopropyl]-3-[[2-(trifluoromethyl)pyrimidin-4-yl]amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	80 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
[(3S,8aS)-3-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-[6,6-dimethyl-3-[(7-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]methanone	KI	84 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-(thieno[3,2-d]pyrimidin-4-ylamino)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	EC50	87 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[(4-chloro-6-propoxy-1,3,5-triazin-2-yl)amino]-6,6-dimethyl-N-(2-phenylcyclopropyl)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	87 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[[4-chloro-6-(dimethylamino)-1,3,5-triazin-2-yl]amino]-6,6-dimethyl-N-(2-phenylcyclopropyl)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	90 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[[4-(2-cyanopyrrolidin-1-yl)-6-methoxy-1,3,5-triazin-2-yl]amino]-6,6-dimethyl-N-(2-phenylcyclopropyl)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	90 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors
3-[[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino]-6,6-dimethyl-N-[(1R,2S)-2-phenylcyclopropyl]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	KI	96 nM	US-8530652: Pyrrolopyrazoles, potent kinase inhibitors

ChEMBL bioactivities

738 potent at pChembl≥5 of 781 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.03	EC50	0.94	nM	CHEMBL3669583
9.00	EC50	1	nM	CHEMBL2064631
9.00	IC50	1	nM	STAUROSPORINE
8.89	IC50	1.3	nM	PF-03758309
8.80	Ki	1.6	nM	CHEMBL3674597
8.80	Ki	1.585	nM	CHEMBL1993661
8.72	Ki	1.9	nM	CHEMBL3674593
8.72	EC50	1.9	nM	CHEMBL3674594
8.72	IC50	1.9	nM	STAUROSPORINE
8.70	Ki	2	nM	CHEMBL3580667
8.62	EC50	2.4	nM	CHEMBL3669628
8.60	EC50	2.5	nM	CHEMBL3669627
8.57	IC50	2.7	nM	CHEMBL5180027
8.57	Kd	2.7	nM	PF-03758309
8.55	Ki	2.8	nM	CHEMBL2064556
8.55	Ki	2.8	nM	CHEMBL3669583
8.52	Ki	3	nM	CHEMBL3669632
8.52	EC50	3	nM	CHEMBL3674593
8.48	Ki	3.3	nM	CHEMBL3128042
8.48	Ki	3.3	nM	CHEMBL5191406
8.46	Ki	3.5	nM	CHEMBL3664542
8.44	Ki	3.6	nM	CHEMBL3674598
8.40	EC50	4	nM	CHEMBL2064628
8.40	Ki	4	nM	CHEMBL3580963
8.40	Ki	4	nM	CHEMBL3580667
8.36	EC50	4.4	nM	CHEMBL3674596
8.35	Kd	4.5	nM	PF-03758309
8.32	IC50	4.77	nM	CHEMBL3128042
8.30	Kd	5	nM	CHEMBL4465866
8.28	IC50	5.3	nM	CHEMBL3355023
8.28	Ki	5.2	nM	CHEMBL3674595
8.28	Ki	5.2	nM	CHEMBL3674599
8.23	IC50	5.9	nM	CHEMBL5175418
8.22	Ki	6	nM	CHEMBL2064555
8.22	Ki	6	nM	CHEMBL4076860
8.22	Kd	6	nM	CHEMBL4076708
8.22	Kd	6	nM	CHEMBL4576489
8.20	Kd	6.3	nM	STAUROSPORINE
8.17	Ki	6.7	nM	CHEMBL3669636
8.15	EC50	7	nM	CHEMBL2064632
8.15	IC50	7	nM	PF-03758309
8.15	Ki	7	nM	CHEMBL4081464
8.14	Ki	7.2	nM	CHEMBL3669607
8.12	IC50	7.5	nM	CHEMBL3128042
8.12	IC50	7.68	nM	CHEMBL6165102
8.10	Kd	8	nM	STAUROSPORINE
8.10	Ki	7.943	nM	CHEMBL1980995
8.10	Ki	7.943	nM	CHEMBL1994669
8.08	Ki	8.3	nM	CHEMBL3674600
8.06	Ki	8.8	nM	CHEMBL3674594

PubChem BioAssay actives

373 with measured affinity, of 3093 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
(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	1646264: Inhibition of PAK4 (unknown origin) by HTRF assay	ic50	0.0010	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-[[1-(trifluoromethyl)cyclobutanecarbonyl]amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0010	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-[(3,3,3-trifluoro-2,2-dimethylpropanoyl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0010	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	1894637: Inhibition of human PAK4 expressed in TR-293-KDG cells assessed as inhibition of GEFH1 phosphorylation at S180 using GEFH1 as substrate incubated for 3 hrs by ELISA	ic50	0.0013	uM
2-[(1S,5R)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine	1229659: Inhibition of human PAK4	ki	0.0020	uM
4-N-(4-aminocyclohexyl)-2-N-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine	1890524: Inhibition of human PAK4 assessed as enzymatic activity incubated for 20 mins by filter binding method	ic50	0.0027	uM
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-3-[6-[(4-pyridin-2-ylphenyl)methylamino]-1H-benzimidazol-2-yl]-1H-indazole-5-carboxamide	675831: Inhibition of PAK4	ki	0.0028	uM
1-[2-[3-(4-amino-1,3,5-triazin-2-yl)-2-(2-methoxyethylamino)benzimidazol-5-yl]ethynyl]cyclohexan-1-ol	1890550: Inhibition of human PAK4 assessed as inhibition constant	ki	0.0033	uM
1-[2-[3-(2-aminopyrimidin-4-yl)-2-(2-methoxyethylamino)benzimidazol-5-yl]ethynyl]cyclohexan-1-ol	1074648: Binding affinity to N-terminal GST-tagged recombinant human PAK4 kinase domain expressed in Escherichia coli using KKRNRRLSVA as substrate preincubated for 10 mins followed by ATP addition measured after 60 mins by FRET-based Z’Lyte assay	ki	0.0033	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-(2,2-dimethylpropanoylamino)-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0040	uM
2-N-[(4-aminocyclohexyl)methyl]-4-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine	1229627: Inhibition of human recombinant PAK4 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
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526198: Binding affinity to recombinant human full-length N-terminal GST-tagged PAK4 expressed in baculovirus expression system using SGKtide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0050	uM
(2R)-4-[3-(4-amino-1,3,5-triazin-2-yl)-2-(ethylamino)benzimidazol-5-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol	1177117: Inhibition of human recombinant PAK4 kinase domain assessed as phosphorylation of FRET peptide substrate at Ser/Thr20 by Zylite assay	ic50	0.0053	uM
6-benzyl-4-N-(5-methyl-1H-pyrazol-3-yl)-2-N-piperidin-4-ylpyrimidine-2,4-diamine	1860523: Inhibition of PAK4 (unknown origin) using S2 as substrate incubated for 60 mins in the presence of ATP by time-resolved HTRF assay	ic50	0.0059	uM
[6-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(3R)-3-ethylpiperazin-1-yl]methanone	1478183: Inhibition of human PAK4 kinase domain using coumarin and fluorescein-labeled ser/thr20 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	ki	0.0060	uM
3-(1H-benzimidazol-2-yl)-N-[(1S)-2-(dimethylamino)-1-phenylethyl]-1H-indazole-5-carboxamide	2171478: Inhibition of PAK4 (unknown origin) assessed as inhibition constant	ki	0.0060	uM
2-(4-aminopiperidin-1-yl)-6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine	1478184: Binding affinity to biotin-labeled human truncated PAK4 kinase domain by surface plasmon resonance assay	kd	0.0060	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526198: Binding affinity to recombinant human full-length N-terminal GST-tagged PAK4 expressed in baculovirus expression system using SGKtide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0060	uM
[7-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(3R)-3-methylpiperazin-1-yl]methanone	1478183: Inhibition of human PAK4 kinase domain using coumarin and fluorescein-labeled ser/thr20 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	ki	0.0070	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0070	uM
[6-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(3R)-3-methylpiperazin-1-yl]methanone	1478183: Inhibition of human PAK4 kinase domain using coumarin and fluorescein-labeled ser/thr20 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	ki	0.0090	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0090	uM
N-[(2S)-2-amino-3-phenylpropyl]-6-chloro-4-(1H-indazol-3-ylamino)quinazoline-2-carboxamide	2037386: Inhibition of PAK4 (unknown origin) using lipid substrate incubated for 40 mins in presence of ATP by ADP-Glo plus luminescence kinase assay	ic50	0.0090	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	391395: Inhibition of human PAK4	ic50	0.0100	uM
N-[(2R)-2-amino-3-methylbutyl]-6-chloro-4-(1H-indazol-3-ylamino)quinazoline-2-carboxamide	2037386: Inhibition of PAK4 (unknown origin) using lipid substrate incubated for 40 mins in presence of ATP by ADP-Glo plus luminescence kinase assay	ic50	0.0100	uM
[6-bromo-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(3R)-3-methylpiperazin-1-yl]methanone	1478183: Inhibition of human PAK4 kinase domain using coumarin and fluorescein-labeled ser/thr20 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	ki	0.0110	uM
N-[(2R)-2-amino-3-phenylpropyl]-6-chloro-4-(1H-indazol-3-ylamino)quinazoline-2-carboxamide	2037386: Inhibition of PAK4 (unknown origin) using lipid substrate incubated for 40 mins in presence of ATP by ADP-Glo plus luminescence kinase assay	ic50	0.0110	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-benzamido-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0110	uM
2-(4-aminopiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine	1229627: Inhibition of human recombinant PAK4 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	0.0120	uM
N-[(2R)-2-amino-2-phenylethyl]-6-chloro-4-(1H-indazol-3-ylamino)quinazoline-2-carboxamide	2037386: Inhibition of PAK4 (unknown origin) using lipid substrate incubated for 40 mins in presence of ATP by ADP-Glo plus luminescence kinase assay	ic50	0.0130	uM
2-N-(3-methoxyphenyl)-4-N-(oxolan-2-ylmethyl)quinazoline-2,4-diamine	1545509: Inhibition of PAK4 (unknown origin) assessed as reduction in histone phosphorylation incubated for 1 hr at 4 degC by immunoblotting analysis	ic50	0.0149	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-[(2,4-difluorobenzoyl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0150	uM
[6-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-piperazin-1-ylmethanone	1478183: Inhibition of human PAK4 kinase domain using coumarin and fluorescein-labeled ser/thr20 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	ki	0.0160	uM
[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-6-fluoroquinazolin-2-yl]-[(3R)-3-methylpiperazin-1-yl]methanone	1478183: Inhibition of human PAK4 kinase domain using coumarin and fluorescein-labeled ser/thr20 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	ki	0.0160	uM
(3Z)-N-[(1S)-2-hydroxy-1-phenylethyl]-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indole-5-carboxamide	1360590: Inhibition of full length human PAK4 using substrate S2 after 60 mins by HTRF assay	ic50	0.0160	uM
N-[(2S)-2-amino-3-methylbutyl]-6-chloro-4-(1H-indazol-3-ylamino)quinazoline-2-carboxamide	2037386: Inhibition of PAK4 (unknown origin) using lipid substrate incubated for 40 mins in presence of ATP by ADP-Glo plus luminescence kinase assay	ic50	0.0160	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-(oxolane-2-carbonylamino)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0160	uM
[6-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(2R)-2-methylpiperazin-1-yl]methanone	1478183: Inhibition of human PAK4 kinase domain using coumarin and fluorescein-labeled ser/thr20 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	ki	0.0170	uM
[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(3R)-3-methylpiperazin-1-yl]methanone	1478183: Inhibition of human PAK4 kinase domain using coumarin and fluorescein-labeled ser/thr20 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	ki	0.0170	uM
3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-(1H-indol-7-ylamino)-1,2,4-triazine-6-carboxamide	1199669: Competitive binding affinity to human PAK4	kd	0.0170	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 6,6-dimethyl-3-(oxane-2-carbonylamino)-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0180	uM
N-[6,6-dimethyl-5-(4-methyl-2-phenylpiperazine-1-carbonyl)-1,4-dihydropyrrolo[3,4-d]pyrazol-3-yl]benzamide	675832: Inhibition of PAK4-mediated GEF-H1 phosphorylation at Ser810 by cell based assay	ec50	0.0210	uM
(3Z)-N-[(1S)-2-hydroxy-1-phenylethyl]-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-1H-indole-5-carboxamide	1453242: Inhibition of PAK4 (unknown origin) using substrate S2 after 60 mins by HTRF assay	ic50	0.0219	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	507659: Binding affinity to PAK4	kd	0.0240	uM
N-[(2S)-2-amino-2-phenylethyl]-6-chloro-4-(1H-indazol-3-ylamino)quinazoline-2-carboxamide	2037386: Inhibition of PAK4 (unknown origin) using lipid substrate incubated for 40 mins in presence of ATP by ADP-Glo plus luminescence kinase assay	ic50	0.0240	uM
(3Z)-N-[(1S)-2-hydroxy-1-phenylethyl]-3-[1H-imidazol-2-yl(phenyl)methylidene]-2-oxo-1H-indole-5-carboxamide	1360590: Inhibition of full length human PAK4 using substrate S2 after 60 mins by HTRF assay	ic50	0.0250	uM
(2S,3R,4R,6R,18S)-18-hydroxy-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	1425100: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0250	uM
[6-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(2S)-2-methylpiperazin-1-yl]methanone	1478183: Inhibition of human PAK4 kinase domain using coumarin and fluorescein-labeled ser/thr20 peptide as substrate preincubated for 15 mins followed by ATP addition measured after 60 mins by Z’-Lyte assay	ki	0.0260	uM
[3-[5-[(2,5-difluorophenyl)methyl]-2H-pyrazolo[3,4-b]pyridin-3-yl]phenyl]-(3-hydroxypiperidin-1-yl)methanone	2139990: Inhibition of PAK4 (unknown origin)	ic50	0.0260	uM
(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-N-[(1S)-2-hydroxy-1-phenylethyl]-2-oxo-1H-indole-5-carboxamide	1453242: Inhibition of PAK4 (unknown origin) using substrate S2 after 60 mins by HTRF assay	ic50	0.0270	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Particulate Matter	decreases expression, decreases reaction	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
lead acetate	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	affects methylation	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	decreases phosphorylation	1
PF 3758309	increases response to substance, decreases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Cadmium	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methapyrilene	increases methylation	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1

ChEMBL screening assays

536 unique, capped per target: 534 binding, 1 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003339	Binding	Inhibition of PAK4 at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem
CHEMBL1963736	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: PAK4	PubChem BioAssay data set
CHEMBL4407580	ADMET	Inhibition of recombinant human GST-tagged PAK4 catalytic domain (295 to 591 residues) expressed in baculovirus expression system at 25 uM using FRET-labeled Ser/Thr 20 peptide as substrate measured after 1 hr by Z’-lyte assay relative to c	Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase. — J Med Chem

Cellosaurus cell lines

11 cell lines: 9 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3DA	Abcam HEK293T PAK4 KO	Transformed cell line	Female
CVCL_B8LY	Abcam HCT 116 PAK4 KO	Cancer cell line	Male
CVCL_B9P4	Abcam A-549 PAK4 KO	Cancer cell line	Male
CVCL_D2GS	Abcam MCF-7 PAK4 KO	Cancer cell line	Female
CVCL_D7WH	Ubigene A-549 PAK4 KO	Cancer cell line	Male
CVCL_D8S0	Ubigene HCT 116 PAK4 KO	Cancer cell line	Male
CVCL_D9M8	Ubigene HEK293 PAK4 KO	Transformed cell line	Female
CVCL_E0JP	Ubigene HeLa PAK4 KO	Cancer cell line	Female
CVCL_TB94	HAP1 PAK4 (-) 1	Cancer cell line	Male
CVCL_TB95	HAP1 PAK4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer