RPS6KA4

Summary

RPS6KA4 (ribosomal protein S6 kinase A4, HGNC:10433) is a protein-coding gene on chromosome 11q13.1, encoding Ribosomal protein S6 kinase alpha-4 (O75676). Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factor RELA, and that contributes to gene activation by histone phosphorylation and function….

This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates various substrates, including CREB1 and ATF1. The encoded protein can also phosphorylate histone H3 to regulate certain inflammatory genes. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8986 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 102 total
• Druggable target: yes — 34 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003942

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10433
Approved symbol	RPS6KA4
Name	ribosomal protein S6 kinase A4
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	RSK-B, MSK2
Ensembl gene	ENSG00000162302
Ensembl biotype	protein_coding
OMIM	603606
Entrez	8986

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 18 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000334205, ENST00000528057, ENST00000528355, ENST00000530383, ENST00000530504, ENST00000531659, ENST00000532496, ENST00000532885, ENST00000891458, ENST00000891459, ENST00000891460, ENST00000891461, ENST00000891462, ENST00000891463, ENST00000891464, ENST00000891465, ENST00000891466, ENST00000891467, ENST00000891468, ENST00000969971, ENST00000969972, ENST00000969973, ENST00000969974

RefSeq mRNA: 4 — MANE Select: NM_003942 NM_001006944, NM_001300802, NM_001318361, NM_003942

CCDS: CCDS73313, CCDS8073

Canonical transcript exons

ENST00000334205 — 17 exons

Exon	Start	End
ENSE00001858230	64371283	64372215
ENSE00001932308	64359162	64359290
ENSE00003473286	64368704	64368797
ENSE00003479341	64365301	64365465
ENSE00003483503	64368132	64368260
ENSE00003487953	64360477	64360592
ENSE00003507824	64369699	64369893
ENSE00003525146	64361852	64362002
ENSE00003530162	64359378	64359449
ENSE00003538814	64361134	64361241
ENSE00003539479	64361469	64361549
ENSE00003570861	64369446	64369619
ENSE00003591677	64360163	64360381
ENSE00003598140	64361642	64361745
ENSE00003623234	64370563	64370726
ENSE00003623574	64368468	64368601
ENSE00003628296	64370225	64370384

Expression profiles

Bgee: expression breadth ubiquitous, 215 present calls, max score 96.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.5793 / max 247.1612, expressed in 1806 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114965	17.2032	1805
114966	1.3187	773
114968	0.0573	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	96.48	gold quality
cerebellar hemisphere	UBERON:0002245	96.09	gold quality
cerebellar cortex	UBERON:0002129	95.93	gold quality
granulocyte	CL:0000094	95.27	gold quality
monocyte	CL:0000576	94.48	gold quality
cerebellum	UBERON:0002037	94.40	gold quality
mononuclear cell	CL:0000842	94.15	gold quality
leukocyte	CL:0000738	94.00	gold quality
right frontal lobe	UBERON:0002810	90.39	gold quality
lower esophagus mucosa	UBERON:0035834	90.36	gold quality
esophagus mucosa	UBERON:0002469	90.22	gold quality
apex of heart	UBERON:0002098	90.18	gold quality
right coronary artery	UBERON:0001625	90.03	gold quality
mucosa of transverse colon	UBERON:0004991	89.45	gold quality
cingulate cortex	UBERON:0003027	88.87	gold quality
prefrontal cortex	UBERON:0000451	88.86	gold quality
anterior cingulate cortex	UBERON:0009835	88.76	gold quality
spleen	UBERON:0002106	88.70	gold quality
metanephros cortex	UBERON:0010533	88.62	gold quality
nucleus accumbens	UBERON:0001882	88.31	gold quality
ileal mucosa	UBERON:0000331	88.26	gold quality
skin of leg	UBERON:0001511	88.22	gold quality
skin of abdomen	UBERON:0001416	87.91	gold quality
esophagus	UBERON:0001043	87.85	gold quality
body of stomach	UBERON:0001161	87.59	gold quality
left coronary artery	UBERON:0001626	87.39	gold quality
transverse colon	UBERON:0001157	87.37	gold quality
caudate nucleus	UBERON:0001873	87.37	gold quality
putamen	UBERON:0001874	87.32	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.29	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	33.59
E-CURD-112	yes	14.15
E-MTAB-9067	yes	13.34
E-CURD-122	yes	12.89
E-ANND-3	yes	5.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, RELA

miRNA regulators (miRDB)

57 targeting RPS6KA4, 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-9-5P	100.00	72.28	2361
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6745	99.74	65.33	1321

Literature-anchored findings (GeneRIF, showing 12)

• Dimethylfumarate specifically inhibits MSK1 and 2 activations and subsequently inhibits NF-kappaB-induced gene-transcriptions, which are believed to be important in the pathogenesis of psoriasis (PMID:17495961)
• MSK1 and MSK2 are differentially regulated by CK2 during the UV response and that MSK2 is the major protein kinase responsible for the UV-induced phosphorylation of p65 at Ser(276) that positively regulates NF-kappaB activity in MDA-MB-231 cells (PMID:19933278)
• MSK1- and MSK2-mediated H3K27me3S28 phosphorylation serves as a mechanism to activate a subset of PcG target genes determined by the biological stimuli and thereby modulate the gene expression program determining cell fate. (PMID:20864036)
• MSK2 functions as an adaptor in mediating PKR activation, apparently independent of its catalytic activity. (PMID:21385567)
• MSK1 and MSK2 are required for maximal TFF 1 induction. (PMID:23675462)
• Data suggest that MSK1 and MSK2 are the major CREB kinases in fibroblast-like synoviocytes from rheumatoid arthritis patients stimulated with lysophosphatidic acid and that phosphorylation of CREB1 at Ser-133 plays a significant role in IL-8 production. (PMID:24792438)
• KSHV activates the MSK1/2-CREB1 pathway during primary infection and that it depends on this pathway for viral lytic replication. I (PMID:26109721)
• Two novel DMRs, located in RPS6KA4/MIR1237 and the AURKC promoter, were found to be hypermethylated in WT (PMID:28930610)
• Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction. (PMID:34445361)
• Mitogen- and stress-activated protein kinase (MSK1/2) regulated gene expression in normal and disease states. (PMID:36812480)
• Potentially functional genetic variants in RPS6KA4 and MAP2K5 in the MAPK signaling pathway predict HBV-related hepatocellular carcinoma survival. (PMID:37278562)
• Comprehensive analysis of the RSK gene family in acute myeloid leukemia determines a prognostic signature for the prediction of clinical prognosis and treatment responses. (PMID:37462338)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	rps6ka4	ENSDARG00000044436
mus_musculus	Rps6ka4	ENSMUSG00000118668
rattus_norvegicus	Rps6ka4	ENSRNOG00000021117
drosophila_melanogaster	JIL-1	FBGN0020412
drosophila_melanogaster	S6k	FBGN0283472
caenorhabditis_elegans	rskn-2	WBGENE00008311
caenorhabditis_elegans		WBGENE00012929
caenorhabditis_elegans		WBGENE00017898
caenorhabditis_elegans		WBGENE00044281

Paralogs (7): RPS6KA2 (ENSG00000071242), RPS6KA6 (ENSG00000072133), RPS6KA5 (ENSG00000100784), RPS6KB1 (ENSG00000108443), RPS6KA1 (ENSG00000117676), RPS6KB2 (ENSG00000175634), RPS6KA3 (ENSG00000177189)

Protein

Protein identifiers

Ribosomal protein S6 kinase alpha-4 — O75676 (reviewed: O75676)

Alternative names: 90 kDa ribosomal protein S6 kinase 4, Nuclear mitogen- and stress-activated protein kinase 2, Ribosomal protein kinase B

All UniProt accessions (4): A0A0A6YYC0, O75676, E9PJN1, E9PKU3

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factor RELA, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF. Phosphorylates ‘Ser-10’ of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate ‘Ser-28’ of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors.

Subunit / interactions. Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells which transiently dissociates following mitogenic stimulation. Also associates with MAPK14/p38-alpha. Activated RPS6KA4 associates with and phosphorylates the NF-kappa-B p65 subunit RELA.

Subcellular location. Nucleus.

Post-translational modifications. Ser-343 and Thr-568 phosphorylation is required for kinase activity. Ser-343 and Ser-196 are autophosphorylated by the C-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain. Phosphorylated at Ser-343, Thr-568 and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha. Autophosphorylated at Ser-737 and Ser-745 by the N-terminal kinase domain.

Activity regulation. Activated by phosphorylation at Ser-343, Thr-568 and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha, and by further autophosphorylation of Ser-196, Ser-360 and Ser-365 by the activated C-terminal kinase domain.

Miscellaneous. Enzyme activity requires the presence of both kinase domains.

Similarity. Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O75676-1	1	yes
O75676-2	2

RefSeq proteins (4): NP_001006945, NP_001287731, NP_001305290, NP_003933* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000961	AGC-kinase_C	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016239	Ribosomal_S6_kinase_II	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR017892	Pkinase_C	Domain
IPR037714	MSK2_N_dom	Domain

Pfam: PF00069, PF00433

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 (31 total): modified residue 12, binding site 4, domain 3, region of interest 3, sequence variant 2, sequence conflict 2, active site 2, chain 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75676-F1	72.00	0.27

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 (2): 161 (proton acceptor); 530 (proton acceptor)

Ligand- & substrate-binding residues (4): 65; 417–425; 440; 39–47

Post-translational modifications (12): 196, 343, 347, 360, 365, 542, 568, 634, 678, 687, 737, 745

Mutagenesis-validated functional residues (1):

Position	Phenotype
709	strongly elevates basal activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-437239	Recycling pathway of L1
R-HSA-1266738	Developmental Biology
R-HSA-373760	L1CAM interactions
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 200 (showing top): CREL_01, PAX4_01, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CREB_TRANSCRIPTION_FACTOR_ACTIVITY, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, AP2_Q3, GGGTGGRR_PAX4_03, chr11q13, GTGCCTT_MIR506, RICKMAN_METASTASIS_DN

GO Biological Process (12): negative regulation of cytokine production (GO:0001818), regulation of DNA-templated transcription (GO:0006355), protein phosphorylation (GO:0006468), inflammatory response (GO:0006954), obsolete positive regulation of CREB transcription factor activity (GO:0032793), intracellular signal transduction (GO:0035556), TORC1 signaling (GO:0038202), post-translational protein modification (GO:0043687), positive regulation of transcription by RNA polymerase II (GO:0045944), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), interleukin-1-mediated signaling pathway (GO:0070498), chromatin remodeling (GO:0006338)

GO Molecular Function (13): magnesium ion binding (GO:0000287), protein serine/threonine kinase activity (GO:0004674), ribosomal protein S6 kinase activity (GO:0004711), ATP binding (GO:0005524), histone H3S10 kinase activity (GO:0035175), histone H3S28 kinase activity (GO:0044022), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
L1CAM interactions	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein serine/threonine kinase activity	3
cellular anatomical structure	3
protein modification process	2
intracellular anatomical structure	2
protein kinase activity	2
histone H3 kinase activity	2
cytokine production	1
regulation of cytokine production	1
negative regulation of gene expression	1
negative regulation of multicellular organismal process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
phosphorylation	1
defense response	1
signal transduction	1
TOR signaling	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-1	1
chromatin organization	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
cell junction	1

Protein interactions and networks

STRING

1160 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPS6KA4	CD58	P19256	565
RPS6KA4	CREB1	P16220	561
RPS6KA4	FOS	P01100	501
RPS6KA4	CD2	P06729	490
RPS6KA4	MAPKAPK2	P49137	418
RPS6KA4	TAF1	P21675	415
RPS6KA4	GTF2E2	P29084	394
RPS6KA4	ELP3	Q9H9T3	358
RPS6KA4	SPI1	P17947	351
RPS6KA4	DENND1B	Q6P3S1	346
RPS6KA4	PLCL2	Q9UPR0	336
RPS6KA4	MACIR	Q96GV9	325
RPS6KA4	FAM228B	P0C875	315
RPS6KA4	MTOR	P42345	315
RPS6KA4	EXOC3L4	Q17RC7	306

IntAct

79 interactions, top by confidence:

A	B	Type	Score
MAPK14	RPS6KA4	psi-mi:“MI:0914”(association)	0.870
MAPK14	RPS6KA4	psi-mi:“MI:0915”(physical association)	0.870
MAPK14	OBSL1	psi-mi:“MI:0914”(association)	0.790
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
CSNK2B	RPS6KA5	psi-mi:“MI:0914”(association)	0.660
MAPK14	RPS6KA5	psi-mi:“MI:0914”(association)	0.660
CSNK2B	NMT2	psi-mi:“MI:0914”(association)	0.660
CSNK2B	RPS6KA4	psi-mi:“MI:0914”(association)	0.640
CLEC4A	SEMA7A	psi-mi:“MI:0914”(association)	0.530
KLHDC3	DPYSL4	psi-mi:“MI:0914”(association)	0.530
MYLK2	RPS6KA4	psi-mi:“MI:0914”(association)	0.530
RPS6KA4	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
NPTN	TNPO2	psi-mi:“MI:0914”(association)	0.530
RPS6KA4	XRCC6	psi-mi:“MI:0915”(physical association)	0.400
MAPK3	RPS6KA4	psi-mi:“MI:0915”(physical association)	0.400
	SGK1	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
RRP1B	ZNF785	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
PRKCB	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
MAPK1	SEC16A	psi-mi:“MI:0914”(association)	0.350

BioGRID (130): RPS6KA4 (Affinity Capture-MS), RPS6KA4 (Affinity Capture-MS), RPS6KA4 (Affinity Capture-MS), RPS6KA4 (Affinity Capture-MS), RPS6KA4 (Co-fractionation), RPS6KA4 (Co-fractionation), RPS6KA4 (Affinity Capture-MS), MAPK1 (Reconstituted Complex), MAPK14 (Reconstituted Complex), RPS6KA4 (Affinity Capture-MS), RPS6KA4 (Affinity Capture-MS), RPS6KA4 (Affinity Capture-MS), RPS6KA4 (Affinity Capture-MS), RPS6KA4 (Negative Genetic), RPS6KA4 (Negative Genetic)

ESM2 similar proteins: A0A0U1RPR8, A0A7N9VSG0, D3ZGQ5, D3ZHP7, O08644, O09127, O15197, O43542, O73875, O73878, O75676, P0C0K6, P0C0K7, P21709, P23800, P29317, P29322, P41243, P51839, P51840, P52785, P54753, P54754, P54760, P54761, P55203, P57078, P97343, Q1KL86, Q3U3Q1, Q4V7Q6, Q5RCY1, Q5ZJH6, Q60750, Q62270, Q63285, Q6PHR2, Q7ZZC8, Q80YD6, Q86SG6

Diamond homologs: A1Z9X0, A2YBX5, F1M7Y5, F4HPN2, F4HYG2, F4I4F2, F4J6F6, O13310, O15021, O42626, O48963, O60307, O64682, O75582, O75676, P09217, P10666, P15792, P18652, P18654, P25341, P28178, P31034, P34099, P34102, P34103, P38938, P41743, P42818, P47197, P51812, P51817, P53739, P53894, P93025, Q02956, Q05513, Q05999, Q09831, Q0DCT8

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
RPS6KA4	up-regulates	ATF1	phosphorylation
RPS6KA4	up-regulates	RELA	phosphorylation
RPS6KA4	up-regulates	RPS6KA4	phosphorylation
CD3G	up-regulates	RPS6KA4
RPS6KA4	up-regulates	CREB1	phosphorylation
RPS6KA4	down-regulates	TP53
RPS6KA4	“up-regulates activity”	FOS	phosphorylation
RPS6KA4	up-regulates	NfKb-p65/p50	phosphorylation
CSNK2A1	“up-regulates activity”	RPS6KA4	phosphorylation
RPS6KA4	“up-regulates activity”	RPS6KA4	phosphorylation
MAPK14	up-regulates	RPS6KA4	phosphorylation
MAPK3	up-regulates	RPS6KA4	phosphorylation
RPS6KA4	“up-regulates activity”	ATF1	phosphorylation
RPS6KA4	unknown	H3-4	phosphorylation
RPS6KA4	unknown	HMGN1	phosphorylation
RPS6KA4	unknown	“Histone H3”	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 92 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
Nuclear Events (kinase and transcription factor activation)	5	28.8×	3e-04
MAP kinase activation	5	25.7×	3e-04
Interleukin-17 signaling	5	21.1×	4e-04
Toll Like Receptor 10 (TLR10) Cascade	5	18.0×	4e-04
Toll Like Receptor 5 (TLR5) Cascade	5	18.0×	4e-04
MyD88 cascade initiated on plasma membrane	5	17.0×	5e-04
Signaling by NTRK1 (TRKA)	5	16.4×	5e-04
Toll Like Receptor 3 (TLR3) Cascade	5	16.1×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
stress-activated MAPK cascade	5	42.3×	7e-05
lipopolysaccharide-mediated signaling pathway	5	31.7×	2e-04
protein phosphorylation	8	6.5×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	76
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2511 predictions. Top by Δscore:

Variant	Effect	Δscore
11:64359287:GAAG:G	donor_gain	1.0000
11:64359289:AGGT:A	donor_loss	1.0000
11:64359291:G:T	donor_loss	1.0000
11:64359376:A:AG	acceptor_gain	1.0000
11:64359377:G:GG	acceptor_gain	1.0000
11:64360149:C:A	acceptor_gain	1.0000
11:64360152:T:A	acceptor_gain	1.0000
11:64360159:ACAGC:A	acceptor_loss	1.0000
11:64360160:CA:C	acceptor_loss	1.0000
11:64360161:A:AG	acceptor_gain	1.0000
11:64360162:G:GC	acceptor_gain	1.0000
11:64360162:GC:G	acceptor_gain	1.0000
11:64360162:GCC:G	acceptor_gain	1.0000
11:64360162:GCCT:G	acceptor_gain	1.0000
11:64360378:CTGG:C	donor_gain	1.0000
11:64360379:TGG:T	donor_gain	1.0000
11:64360379:TGGGT:T	donor_loss	1.0000
11:64360380:GG:G	donor_gain	1.0000
11:64360380:GGG:G	donor_gain	1.0000
11:64360380:GGGTG:G	donor_loss	1.0000
11:64360381:GG:G	donor_gain	1.0000
11:64360382:G:C	donor_loss	1.0000
11:64360382:G:GG	donor_gain	1.0000
11:64360465:T:A	acceptor_gain	1.0000
11:64360468:A:AG	acceptor_gain	1.0000
11:64360475:A:AG	acceptor_gain	1.0000
11:64360475:AGACT:A	acceptor_loss	1.0000
11:64360476:G:GA	acceptor_gain	1.0000
11:64360476:GA:G	acceptor_gain	1.0000
11:64360476:GAC:G	acceptor_gain	1.0000

AlphaMissense

4973 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:64359440:G:C	G40R	1.000
11:64360181:T:C	L49P	1.000
11:64360228:A:C	K65Q	1.000
11:64360230:G:C	K65N	1.000
11:64360230:G:T	K65N	1.000
11:64360373:T:C	L113P	1.000
11:64360491:G:T	G121W	1.000
11:64360492:G:T	G121V	1.000
11:64360500:T:C	F124L	1.000
11:64360502:C:A	F124L	1.000
11:64360502:C:G	F124L	1.000
11:64361150:G:C	R160P	1.000
11:64361153:A:C	D161A	1.000
11:64361153:A:G	D161G	1.000
11:64361153:A:T	D161V	1.000
11:64361154:C:A	D161E	1.000
11:64361154:C:G	D161E	1.000
11:64361164:G:A	E165K	1.000
11:64361165:A:T	E165V	1.000
11:64361167:A:G	N166D	1.000
11:64361168:A:T	N166I	1.000
11:64361169:T:A	N166K	1.000
11:64361169:T:G	N166K	1.000
11:64361206:G:C	D179H	1.000
11:64361207:A:C	D179A	1.000
11:64361207:A:G	D179G	1.000
11:64361207:A:T	D179V	1.000
11:64361208:C:A	D179E	1.000
11:64361208:C:G	D179E	1.000
11:64361216:T:C	L182P	1.000

dbSNP variants (sampled 300 via entrez): RS1000088558 (11:64361344 T>C,G), RS1001250935 (11:64361409 G>C), RS1001605310 (11:64367366 A>G), RS1001917583 (11:64370530 GCTCCTCCCCACA>G), RS1002361819 (11:64368321 A>G), RS1002976217 (11:64363316 G>A), RS1003031408 (11:64363525 C>G,T), RS1003258406 (11:64364457 G>T), RS1003431376 (11:64358254 C>T), RS1003600611 (11:64370274 G>T), RS1003719991 (11:64364840 A>G), RS1004105434 (11:64367274 T>C,G), RS1004323380 (11:64366960 C>T), RS1004673303 (11:64364927 A>G,T), RS1004692298 (11:64370895 G>C)

Disease associations

OMIM: gene MIM:603606 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001010_20	Primary biliary cholangitis	2.000000e-10
GCST001292_2	Leprosy	7.000000e-06
GCST001725_12	Inflammatory bowel disease	4.000000e-11
GCST004132_98	Crohn’s disease	5.000000e-06
GCST005527_14	Psoriasis	2.000000e-06
GCST005581_39	Primary biliary cirrhosis	2.000000e-07
GCST008363_120	Offspring birth weight	3.000000e-08
GCST010512_11	Serum uric acid levels	1.000000e-12
GCST011837_4	Cervical high-risk human papilloma virus infection	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004267	biliary liver cirrhosis
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004761	uric acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3125 (SINGLE PROTEIN), CHEMBL3832633 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

34 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 384,718 (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
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL939	GEFITINIB	4	117,814
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL274654	ORANTINIB	3	3,596
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1090089	PAMAPIMOD	2	428
CHEMBL1721885	SU-014813	2	363
CHEMBL1738757	REBASTINIB	2	1,478
CHEMBL2386889	SCH-900776	2	740
CHEMBL475251	R-406	2	762
CHEMBL495727	AT-9283	2	1,376
CHEMBL513909	BI-2536	2
CHEMBL1230122	R-1487	1
CHEMBL1908394	GSK-461364	1
CHEMBL1908397	KW-2449	1
CHEMBL2041933	AZD-7762	1
CHEMBL2140408	AMG-900	1
CHEMBL3128043	PF-03758309	1
CHEMBL3544932	TAK-901	1
CHEMBL3544966	GSK-1059615	1
CHEMBL4289017	PF-03814735	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — MSK subfamily

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 23 [PMID: 35816678]	Inhibition	7.07	pIC50
compound 8 [PMID: 17480064]	Inhibition	5.52	pIC50

Binding affinities (BindingDB)

14 measured of 14 human assays (14 total across all organisms); most potent 14 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
Pyrrolopyridine, 16	IC50	8.5 nM
JMC502647 Compound 8	IC50	10 nM
Pyrrolopyridine, 9	IC50	66 nM
Pyrrolopyridine, 23	IC50	126 nM
PKC-412	KD	190 nM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methyl-phenyl)urea	KD	450 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 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
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM

ChEMBL bioactivities

120 potent at pChembl≥5 of 122 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.74	IC50	1.82	nM	STAUROSPORINE
8.53	IC50	2.98	nM	STAUROSPORINE
8.42	IC50	3.79	nM	CHEMBL3909070
8.12	IC50	7.58	nM	CHEMBL3927587
8.06	Kd	8.766	nM	CHEMBL3752910
8.00	IC50	10	nM	AT-9283
7.99	IC50	10.3	nM	CHEMBL3924878
7.95	IC50	11.3	nM	STAUROSPORINE
7.92	IC50	12	nM	AT-13148
7.92	Kd	12	nM	BI-2536
7.90	IC50	12.7	nM	CHEMBL3911801
7.85	ED50	14.2	nM	CHEMBL3752910
7.70	IC50	19.95	nM	CHEMBL5184056
7.70	Ki	19.95	nM	CHEMBL1987679
7.55	Kd	28	nM	LESTAURTINIB
7.53	IC50	29.4	nM	CHEMBL3889534
7.40	Ki	39.81	nM	CHEMBL2002726
7.36	Kd	44	nM	R-406
7.30	Ki	50.12	nM	LINIFANIB
7.29	Kd	51	nM	GSK-690693
7.21	Kd	62	nM	LESTAURTINIB
7.20	Ki	63.1	nM	CHEMBL1990885
7.19	Kd	65	nM	CHEMBL1241674
7.17	IC50	66.82	nM	CHEMBL5423601
7.14	Kd	73	nM	AT-9283
7.14	Kd	73	nM	R-1487
7.10	IC50	79.43	nM	CHEMBL5190298
7.10	Ki	79.43	nM	CHEMBL1998585
7.03	Kd	94	nM	HESPERADIN
7.02	Kd	95.15	nM	CHEMBL5653589
7.02	Kd	96	nM	SUNITINIB
7.00	Ki	100	nM	CHEMBL4249925
7.00	Ki	100	nM	CHEMBL1964687
7.00	Ki	100	nM	CHEMBL220057
6.96	Kd	111	nM	PF-03758309
6.96	Kd	111	nM	CHEMBL3688339
6.92	Kd	120	nM	STAUROSPORINE
6.90	Ki	125.9	nM	CHEMBL2001257
6.85	Kd	140	nM	SUNITINIB
6.85	Kd	140	nM	FEDRATINIB
6.82	Kd	150	nM	PAMAPIMOD
6.81	Kd	156	nM	PF-03814735
6.81	ED50	154.1	nM	CHEMBL5653589
6.80	Ki	158.5	nM	CHEMBL271381
6.80	Ki	158.5	nM	CHEMBL394619
6.70	Kd	200	nM	SU-014813
6.70	Ki	199.5	nM	CHEMBL1979883
6.70	Ki	199.5	nM	CHEMBL1973937
6.60	Ki	251.2	nM	CHEMBL1973211
6.60	Ki	251.2	nM	CHEMBL404367

PubChem BioAssay actives

91 with measured affinity, of 1207 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	2198328: Inhibition of human MSK2 using GRPRTSSFAEG as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.0018	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149312: Binding affinity to human RPS6KA4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0088	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	412618: Inhibition of Rsk4	ic50	0.0100	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	0.0120	uM
6-chloro-2-pyrrolo[3,2-d]pyrimidin-5-ylpyridine-3-carbonitrile	1893506: Inhibition of MSK2 (unknown origin) FAM-PSKPAATRKRRWSAPESR-NH2 as substrate preincubated for 1 hr followed by activation with ERK2 and substrate addition measured after 2 hrs by microfluidic chip based electrophoresis	ic50	0.0199	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	508071: Binding affinity to RPS6KA1(Kin.Dom.1-N-terminal)	kd	0.0280	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	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	0.0440	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	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	0.0510	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	0.0650	uM
N-[3-cyclopropyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl]-5-methyl-18-oxo-9-oxa-17,23,25,26-tetrazatetracyclo[17.5.2.14,8.022,25]heptacosa-1(24),4,6,8(27),19(26),20,22-heptaen-2-yne-6-carboxamide	2014053: Inhibition of P70S6K (unknown origin)	ic50	0.0668	uM
6-(2,4-difluorophenoxy)-8-methyl-2-(oxan-4-ylamino)pyrido[2,3-d]pyrimidin-7-one	592376: Inhibition of RSK4	kd	0.0730	uM
5-(4-chloropyrimidin-2-yl)pyrrolo[3,2-d]pyrimidine	1893506: Inhibition of MSK2 (unknown origin) FAM-PSKPAATRKRRWSAPESR-NH2 as substrate preincubated for 1 hr followed by activation with ERK2 and substrate addition measured after 2 hrs by microfluidic chip based electrophoresis	ic50	0.0794	uM
N-[2-hydroxy-3-[C-phenyl-N-[4-(piperidin-1-ylmethyl)phenyl]carbonimidoyl]-1H-indol-5-yl]ethanesulfonamide	389046: Binding affinity to human MSK2	kd	0.0940	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149312: Binding affinity to human RPS6KA4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0951	uM
Sunitinib	435325: Binding constant for RPS6KA4(Kin.Dom.1 - C-terminal) kinase domain	kd	0.0960	uM
2-[3-(methanesulfonamido)phenyl]-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,3-thiazol-2-yl]acetamide	1398932: Inhibition of p70S6K (unknown origin)	ki	0.1000	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425161: 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	0.1110	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	1425161: 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	0.1110	uM
Fedratinib	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	0.1400	uM
6-(2,4-difluorophenoxy)-2-(1,5-dihydroxypentan-3-ylamino)-8-methylpyrido[2,3-d]pyrimidin-7-one	592376: Inhibition of RSK4	kd	0.1500	uM
N-[2-[4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl]-2-oxoethyl]acetamide	1425161: 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	0.1560	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	435325: Binding constant for RPS6KA4(Kin.Dom.1 - C-terminal) kinase domain	kd	0.2000	uM
Midostaurin	435325: Binding constant for RPS6KA4(Kin.Dom.1 - C-terminal) kinase domain	kd	0.2600	uM
Ruxolitinib	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	0.3400	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	1425161: 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	0.4200	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-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-nonaene-16-carboxylate	1425161: 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	0.4320	uM
(5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione	1425161: 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	0.4990	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624806: Binding constant for RPS6KA4(Kin.Dom.1-N-terminal) kinase domain	kd	0.6200	uM
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	0.7400	uM
1-(2,5-dichloropyrimidin-4-yl)pyrrolo[3,2-b]pyridine	1893506: Inhibition of MSK2 (unknown origin) FAM-PSKPAATRKRRWSAPESR-NH2 as substrate preincubated for 1 hr followed by activation with ERK2 and substrate addition measured after 2 hrs by microfluidic chip based electrophoresis	ic50	0.7943	uM
4-N-(3-aminopropyl)-2-N-(2-methylsulfonyl-3,4-dihydro-1H-isoquinolin-6-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine	2026722: Inhibition of p70S6K (unknown origin) using peptide substrate incubated for 1 hrs in presence of ATP by fluorescence microplate reader	ic50	0.8348	uM
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide	1425161: 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	0.8790	uM
7-chloro-3-oxo-8-(1,3-thiazol-5-ylmethylamino)-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,17(21),18-hexaene-18-carbonitrile	310375: Inhibition of MSK2	ki	0.9490	uM
2-amino-2-cyclohexyl-N-[2-(1-methylpyrazol-4-yl)-9-oxo-3,10,11-triazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13),11-pentaen-6-yl]acetamide	1425161: 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	1.0550	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	1.1000	uM
Gefitinib	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	1.2000	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	435325: Binding constant for RPS6KA4(Kin.Dom.1 - C-terminal) kinase domain	kd	1.3000	uM
3-[2,4-dimethyl-5-[(Z)-(2-oxo-1H-indol-3-ylidene)methyl]-1H-pyrrol-3-yl]propanoic acid	1425161: 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	1.3880	uM
3-[3-[N-[4-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-1H-indol-6-yl]-N-ethylprop-2-ynamide	1425161: 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	1.4590	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435325: Binding constant for RPS6KA4(Kin.Dom.1 - C-terminal) kinase domain	kd	1.9000	uM
N-[4-[[3-(2-aminopyrimidin-4-yl)-2-pyridinyl]oxy]phenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine	1425161: 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	2.0690	uM
N’-(1,8-dimethylimidazo[1,2-a]quinoxalin-4-yl)ethane-1,2-diamine	624927: Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain	kd	2.3000	uM
8-[2-methoxy-5-(4-methylpiperazin-1-yl)anilino]-1-methyl-4,5-dihydropyrazolo[4,5-h]quinazoline-3-carboxamide	1425161: 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	2.4550	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	624806: Binding constant for RPS6KA4(Kin.Dom.1-N-terminal) kinase domain	kd	2.5000	uM
3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione	624806: Binding constant for RPS6KA4(Kin.Dom.1-N-terminal) kinase domain	kd	2.5000	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435325: Binding constant for RPS6KA4(Kin.Dom.1 - C-terminal) kinase domain	kd	3.0000	uM
5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide	1425161: 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	3.0040	uM
2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one	1799072: Kinase Selectivity Assay from Article 10.1021/jm0611004: “Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2).”	ic50	3.0100	uM
1-(4-chloropyrimidin-2-yl)pyrrolo[3,2-b]pyridine	1893506: Inhibition of MSK2 (unknown origin) FAM-PSKPAATRKRRWSAPESR-NH2 as substrate preincubated for 1 hr followed by activation with ERK2 and substrate addition measured after 2 hrs by microfluidic chip based electrophoresis	ic50	3.1623	uM
2-chloro-6-pyrrolo[3,2-d]pyrimidin-5-ylpyridine-3-carbonitrile	1893506: Inhibition of MSK2 (unknown origin) FAM-PSKPAATRKRRWSAPESR-NH2 as substrate preincubated for 1 hr followed by activation with ERK2 and substrate addition measured after 2 hrs by microfluidic chip based electrophoresis	ic50	3.1623	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, increases abundance, increases expression	3
bisphenol S	decreases methylation, affects cotreatment, increases expression	2
Nickel	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
propylparaben	increases expression	1
lead acetate	increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
cobaltous chloride	decreases expression	1
ferrous chloride	decreases expression	1
cupric chloride	increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
obeticholic acid	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Chelating Agents	affects binding, decreases expression	1

ChEMBL screening assays

389 unique, capped per target: 387 binding, 1 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1009917	Binding	Inhibition of Rsk4	Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. — J Med Chem
CHEMBL1963732	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: RPS6KA4	PubChem BioAssay data set
CHEMBL4424897	ADMET	Inhibition of human full-length N-terminal His-tagged p70S6K expressed in baculovirus infected Sf21 insect cells using CKRRRLASLR as substrate	Optimization of an azetidine series as inhibitors of colony stimulating factor-1 receptor (CSF-1R) Type II to lead to the clinical candidate JTE-952. — Bioorg Med Chem Lett

Cellosaurus cell lines

8 cell lines: 7 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8UT	Ubigene HCT 116 RPS6KA4 KO	Cancer cell line	Male
CVCL_D9QX	Ubigene HEK293 RPS6KA4 KO	Transformed cell line	Female
CVCL_DX53	HAP1 RPS6KA4 (-) RPS6KA5 (-) 1	Cancer cell line	Male
CVCL_DX54	HAP1 RPS6KA4 (-) RPS6KA5 (-) 2	Cancer cell line	Male
CVCL_DX55	HAP1 RPS6KA4 (-) RPS6KA5 (-) 3	Cancer cell line	Male
CVCL_TJ63	HAP1 RPS6KA4 (-) 1	Cancer cell line	Male
CVCL_TJ64	HAP1 RPS6KA4 (-) 2	Cancer cell line	Male
CVCL_TJ65	HAP1 RPS6KA4 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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