RPS6KA3

Summary

RPS6KA3 (ribosomal protein S6 kinase A3, HGNC:10432) is a protein-coding gene on chromosome Xp22.12, encoding Ribosomal protein S6 kinase alpha-3 (P51812). Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and…. It is haploinsufficient (ClinGen: sufficient evidence).

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 members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Mutations in this gene have been associated with Coffin-Lowry syndrome (CLS).

Source: NCBI Gene 6197 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Coffin-Lowry syndrome (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 738 total — 110 pathogenic, 57 likely-pathogenic
• Phenotypes (HPO): 129
• Druggable target: yes — 46 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004586

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10432
Approved symbol	RPS6KA3
Name	ribosomal protein S6 kinase A3
Location	Xp22.12
Locus type	gene with protein product
Status	Approved
Aliases	RSK2, HU-3
Ensembl gene	ENSG00000177189
Ensembl biotype	protein_coding
OMIM	300075
Entrez	6197

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 24 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000379565, ENST00000438357, ENST00000457145, ENST00000474266, ENST00000479809, ENST00000642835, ENST00000643073, ENST00000643085, ENST00000643337, ENST00000643402, ENST00000644368, ENST00000644893, ENST00000645268, ENST00000645270, ENST00000646610, ENST00000647265, ENST00000916291, ENST00000916292, ENST00000916293, ENST00000916294, ENST00000916295, ENST00000952698, ENST00000952699, ENST00000952700, ENST00000952701, ENST00000952702, ENST00000952703

RefSeq mRNA: 1 — MANE Select: NM_004586 NM_004586

CCDS: CCDS14197

Canonical transcript exons

ENST00000379565 — 22 exons

Exon	Start	End
ENSE00001242451	20188497	20188534
ENSE00001481681	20266564	20266909
ENSE00001621209	20172746	20172871
ENSE00001712079	20176250	20176352
ENSE00001716454	20176996	20177084
ENSE00001716898	20164899	20165060
ENSE00001745147	20186296	20186366
ENSE00001770840	20176434	20176498
ENSE00001779550	20175164	20175288
ENSE00001794180	20193487	20193593
ENSE00001886538	20149911	20155520
ENSE00002302548	20187828	20187970
ENSE00003480284	20167589	20167747
ENSE00003497750	20161644	20161761
ENSE00003518598	20195065	20195145
ENSE00003522149	20156109	20156249
ENSE00003538112	20162964	20163040
ENSE00003636916	20204022	20204103
ENSE00003664107	20234758	20234814
ENSE00003664671	20194189	20194268
ENSE00003669419	20169402	20169491
ENSE00003689312	20209288	20209404

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.8984 / max 543.1891, expressed in 1809 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198684	20.6633	1774
198686	6.8272	1700
198685	1.2524	864
198676	1.1331	288
198682	0.5746	299
198683	0.2135	58
198677	0.1966	90
198678	0.0212	11
198679	0.0165	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	97.33	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.85	gold quality
colonic mucosa	UBERON:0000317	95.38	gold quality
biceps brachii	UBERON:0001507	95.35	gold quality
triceps brachii	UBERON:0001509	94.45	gold quality
islet of Langerhans	UBERON:0000006	94.42	gold quality
deltoid	UBERON:0001476	93.93	gold quality
gastrocnemius	UBERON:0001388	93.92	gold quality
quadriceps femoris	UBERON:0001377	93.84	gold quality
gluteal muscle	UBERON:0002000	93.84	gold quality
muscle of leg	UBERON:0001383	93.81	gold quality
muscle organ	UBERON:0001630	93.80	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.71	gold quality
calcaneal tendon	UBERON:0003701	93.68	gold quality
vastus lateralis	UBERON:0001379	93.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.60	gold quality
jejunal mucosa	UBERON:0000399	93.27	gold quality
skeletal muscle tissue	UBERON:0001134	93.26	gold quality
tibialis anterior	UBERON:0001385	93.25	gold quality
monocyte	CL:0000576	93.24	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.18	gold quality
mononuclear cell	CL:0000842	92.95	gold quality
leukocyte	CL:0000738	92.83	gold quality
rectum	UBERON:0001052	92.70	gold quality
skin of hip	UBERON:0001554	92.07	gold quality
gall bladder	UBERON:0002110	91.89	gold quality
ileal mucosa	UBERON:0000331	91.80	gold quality
colonic epithelium	UBERON:0000397	91.73	gold quality
jejunum	UBERON:0002115	91.63	gold quality
seminal vesicle	UBERON:0000998	91.25	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	19.29
E-HCAD-10	yes	6.77
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, ATF4, FOXO1, NFKBIA, NR3C1, YBX1

miRNA regulators (miRDB)

307 targeting RPS6KA3, 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-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-186-5P	99.99	70.83	3707
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-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4789-3P	99.99	70.75	2484

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Mutations cause X-linked Coffin-Lowry Syndrome, a mental retardation syndrome. (PMID:11896450)
• Unusual splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity in Coffin-Lowry syndrome (PMID:11992250)
• Molecular crosstalk between p70S6k and MAPK cell signaling pathways (PMID:12054624)
• This protein is mutated in ataxia telangiectasia and is involved in the phoshphorylation of STAT3. (PMID:12562765)
• Postmortem fundings in the CLS syndrome are presented. (PMID:12792428)
• activity is regulated by interaction with PEA-15 (PMID:12796492)
• Expression pattern during development suggests it may be involved in cognitive impairment and facial dysmorphisms found in Coffin-Lowry Syndrome. (PMID:14678837)
• Investigation of the mechanisms underlying aberrant splicing of RSK2 mRNA. (PMID:14973203)
• RSK2 levels are higher in human prostate cancers compared with normal prostate; increased RSK2 levels may participate in the rise in PSA expression seen in prostate cancer. Proliferation of prostate cancer cells may be dependent on RSK2 activity. (PMID:15833840)
• A novel RSK2 (RPS6KA3) gene mutation is associated with abnormal brain MRI findings in a family with Coffin-Lowry syndrome. (PMID:16691578)
• we present 44 novel mutations in RSK2 gene causing Coffin-Lowry syndrome (PMID:16879200)
• Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation. (PMID:17100996)
• RSK2 is an important kinase for NFAT3 in mediating myotube differentiation (PMID:17213202)
• Data identify a novel reciprocal regulation of Tat and RSK2 function, which might serve to induce early changes in the chromatin organization of the HIV LTR. (PMID:17225856)
• Cerebellum and hippocampus volumes were particularly impacted by Coffin-Lowry syndrome and may be associated with specific interfamilial RSK2 mutations. (PMID:17318637)
• an essential nonredundant role of Rsk2 in T-cell activation. (PMID:17938253)
• Src-dependent phosphorylation at Tyr-529 facilitates inactive ERK binding to RSK2, which might be a general requirement for RSK2 activation by EGF through the MEK/ERK pathway. (PMID:18156174)
• RSK1 and RSK2 are required for Raptor phosphorylation in vivo and directly phosphorylate Raptor in vitro. (PMID:18722121)
• Reults describe codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival. (PMID:18775331)
• The authors found that knockdown of RSK2 enhanced influenza virus polymerase activity and growth of influenza viruses. (PMID:19129453)
• betaTrCP promotes cell survival in cooperation with the ERK-RSK pathway by targeting BimEL for degradation. (PMID:19150432)
• Targeting RSK2 with natural compounds, such as kaempferol, in cancer cells may be a good strategy for chemopreventive or chemotherapeutic application. (PMID:19435896)
• RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells. (PMID:19716794)
• p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells. (PMID:20234090)
• the involvement of Rsk2 in the activation and maintenance of the spindle assembly checkpoint in metaphase II-arrested Xenopus egg extracts and in human cells (PMID:20383198)
• Data show that RSK2 is activated by treatment with tumor necrosis factor-alpha (TNF-alpha) and directly phosphorylates IkappaBalpha at Ser-32, leading to IkappaBalpha degradation. (PMID:20385620)
• RSK2 could regulate neurotransmitter release by activating phospholipase D production of lipids required for exocytosis. (PMID:21061166)
• data provide a direct link between RSK2 and caspase-8 and identify a novel molecular mechanism for caspase-8 modulation by RSK2 (PMID:21183680)
• Data show that SH3P2 was phosphorylated on Ser(202) by ribosomal S6 kinase (RSK) in an ERK pathway-dependent manner, and such phosphorylation inhibited the ability of SH3P2 to suppress cell motility. (PMID:21501342)
• MSP-induced RSK2 activation is a critical determinant linking RON signaling to cellular EMT program. (PMID:21619683)
• To our knowledge, this is the first family identified with a submicroscopic duplication including the entire RPS6KA3/RSK2 gene, and our findings suggest that an increased dose of this gene is responsible for a mild form of NS-XLID. (PMID:21930553)
• the results highlight a novel role for RSK1/2 and HSP27 phosphoproteins in P. aeruginosa-dependent induction of transcription of the IL-8 gene in human bronchial epithelial cells. (PMID:22031759)
• Epidermal growth factor (EGF) induces ribosomal S6 kinase 2 (RSK2) ubiquitination, and knocking down TRAF2 suppresses ubiquitination of RSK2 induced by EGF (PMID:22685297)
• RSK2 plays a key role in neoplastic transformation of human skin cells and in skin cancer growth. (PMID:22918890)
• Results indicate that RSK2 is regulated in response to cisplatin treatment, and this downregulation may contribute to the cytotoxic action of cisplatin. (PMID:23041051)
• These results reveal RSK2 as a key regulator of integrin activity and provide a novel mechanism by which it may promote cell migration and cancer metastasis. (PMID:23118220)
• ILKAP is a nuclear protein that regulates cell survival and apoptosis through the regulation of RSK2 signaling. (PMID:23329845)
• Data indicate that the N-terminal kinase domain of p90 ribosomal S6 kinase, isoform 2, binds three different flavonol rhamnosides in a highly unusual manner, distinct from other kinase inhibitor interactions. (PMID:23541530)
• RSK2 functions as a signal integrator to provide antianoikis protection to cancer cells in both transcription-independent and -dependent manners, in part by signaling through ASK1 and CREB, and contributes to cancer cell invasion and tumor metastasis. (PMID:23608533)
• protein effectors of the RSK2-CREB-Fascin-1 pathway represent promising biomarkers and therapeutic targets in the clinical prognosis and treatment of metastatic human cancers. (PMID:24085294)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	rps6ka3a	ENSDARG00000035556
danio_rerio	rps6ka3b	ENSDARG00000057927
mus_musculus	Rps6ka3	ENSMUSG00000031309
rattus_norvegicus	Rps6ka3	ENSRNOG00000006632
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), RPS6KA4 (ENSG00000162302), RPS6KB2 (ENSG00000175634)

Protein

Protein identifiers

Ribosomal protein S6 kinase alpha-3 — P51812 (reviewed: P51812)

Alternative names: 90 kDa ribosomal protein S6 kinase 3, Insulin-stimulated protein kinase 1, MAP kinase-activated protein kinase 1b, Ribosomal S6 kinase 2, pp90RSK2

All UniProt accessions (9): A0A2R8Y603, A0A2R8Y7S9, A0A2R8YGB7, A0A384MDW3, B1AXG1, B1AXG2, B4DG22, B7ZB17, P51812

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at ‘Ser-10’, which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at ‘Ser-9’ and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at ‘Ser-1798’, which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. Negatively regulates EGF-induced MAPK1/3 phosphorylation via phosphorylation of SOS1. Phosphorylates SOS1 at ‘Ser-1134’ and ‘Ser-1161’ that create YWHAB and YWHAE binding sites and which contribute to the negative regulation of MAPK1/3 phosphorylation. Phosphorylates EPHA2 at ‘Ser-897’, the RPS6KA-EPHA2 signaling pathway controls cell migration. Acts as a regulator of osteoblast differentiation by mediating phosphorylation of ATF4, thereby promoting ATF4 transactivation activity.

Subunit / interactions. Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation. Interacts with NFATC4, ETV1/ER81 and FGFR1.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in many tissues, highest levels in skeletal muscle.

Post-translational modifications. Activated by phosphorylation at Ser-227 by PDPK1. Autophosphorylated on Ser-386, as part of the activation process. May be phosphorylated at Thr-365 and Ser-369 by MAPK1/ERK2 and MAPK3/ERK1. Can also be activated via phosphorylation at Ser-386 by MAPKAPK2. N-terminal myristoylation results in an activated kinase in the absence of added growth factors.

Disease relevance. Coffin-Lowry syndrome (CLS) [MIM:303600] An X-linked disorder characterized by intellectual disability associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders. The disease is caused by variants affecting the gene represented in this entry. Intellectual developmental disorder, X-linked 19 (XLID19) [MIM:300844] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Upon extracellular signal or mitogen stimulation, phosphorylated at Thr-577 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-386, allowing binding of PDPK1, which in turn phosphorylates Ser-227 in the N-terminal kinase domain (NTDK) leading to the full activation of the protein and subsequent phosphorylation of the substrates by the NTKD.

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

RefSeq proteins (1): NP_004577* (*=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
IPR041905	RPS6KA3_C	Domain
IPR041906	RSK_N	Domain

Pfam: PF00069, PF00433

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 (109 total): helix 32, strand 22, sequence variant 21, modified residue 9, turn 8, sequence conflict 5, binding site 4, domain 3, active site 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
4NW6	X-RAY DIFFRACTION	1.74
8EQ5	X-RAY DIFFRACTION	1.8
4NW5	X-RAY DIFFRACTION	1.94
5D9L	X-RAY DIFFRACTION	2.15
8R58	X-RAY DIFFRACTION	2.31
4NUS	X-RAY DIFFRACTION	2.39
4D9T	X-RAY DIFFRACTION	2.4
4D9U	X-RAY DIFFRACTION	2.4
5D9K	X-RAY DIFFRACTION	2.55
4JG6	X-RAY DIFFRACTION	2.6
8XEY	X-RAY DIFFRACTION	2.65
7OPO	X-RAY DIFFRACTION	2.75
4JG7	X-RAY DIFFRACTION	3
4JG8	X-RAY DIFFRACTION	3.1
8XFY	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51812-F1	76.72	0.37

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): 193 (proton acceptor); 539 (proton acceptor)

Ligand- & substrate-binding residues (4): 428–436; 451; 74–82; 100

Post-translational modifications (9): 227, 365, 369, 375, 386, 415, 529, 556, 715

Function

Pathways and Gene Ontology

Reactome pathways

50 pathways

ID	Pathway
R-HSA-198753	ERK/MAPK targets
R-HSA-199920	CREB phosphorylation
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-437239	Recycling pathway of L1
R-HSA-442742	CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling
R-HSA-444257	RSK activation
R-HSA-881907	Gastrin-CREB signalling pathway via PKC and MAPK
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-166520	Signaling by NTRKs
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)

MSigDB gene sets: 672 (showing top): RNGTGGGC_UNKNOWN, RRAGTTGT_UNKNOWN, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, XU_GH1_AUTOCRINE_TARGETS_UP, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_GROWTH, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, AP2_Q3, GGGTGGRR_PAX4_03

GO Biological Process (15): skeletal system development (GO:0001501), toll-like receptor signaling pathway (GO:0002224), regulation of DNA-templated transcription (GO:0006355), signal transduction (GO:0007165), chemical synaptic transmission (GO:0007268), central nervous system development (GO:0007417), positive regulation of cell growth (GO:0030307), response to lipopolysaccharide (GO:0032496), TORC1 signaling (GO:0038202), negative regulation of apoptotic process (GO:0043066), regulation of translation in response to stress (GO:0043555), positive regulation of cell differentiation (GO:0045597), positive regulation of transcription by RNA polymerase II (GO:0045944), protein phosphorylation (GO:0006468), intracellular signal transduction (GO:0035556)

GO Molecular Function (12): magnesium ion binding (GO:0000287), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ribosomal protein S6 kinase activity (GO:0004711), ATP binding (GO:0005524), protein kinase binding (GO:0019901), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), synapse (GO:0045202), nucleus (GO:0005634), ribosome (GO:0005840)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Toll-like Receptor Cascades	4
Nuclear Events (kinase and transcription factor activation)	2
MAPK targets/ Nuclear events mediated by MAP kinases	2
Toll Like Receptor 4 (TLR4) Cascade	2
Cellular Senescence	1
L1CAM interactions	1
Post NMDA receptor activation events	1
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1
G alpha (q) signalling events	1
Transmission across Chemical Synapses	1
Neuronal System	1
Immune System	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Signaling by Receptor Tyrosine Kinases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
system development	2
positive regulation of cellular process	2
intracellular anatomical structure	2
protein kinase activity	2
nuclear lumen	2
intracellular membraneless organelle	2
pattern recognition receptor signaling pathway	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
anterograde trans-synaptic signaling	1
nervous system development	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
TOR signaling	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
translation	1
regulation of translation	1
cellular response to stress	1
cell differentiation	1
regulation of cell differentiation	1
positive regulation of developmental process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
phosphorylation	1
protein modification process	1
signal transduction	1

Protein interactions and networks

STRING

2178 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPS6KA3	TIA1	P31483	887
RPS6KA3	CREB1	P16220	759
RPS6KA3	PEA15	Q15121	721
RPS6KA3	RPS6	P08227	620
RPS6KA3	TSC2	P49815	611
RPS6KA3	ESR1	P03372	588
RPS6KA3	RANBP3	Q9H6Z4	579
RPS6KA3	PTPN11	Q06124	576
RPS6KA3	H3-3A	P06351	572
RPS6KA3	H3C1	P02295	572
RPS6KA3	MTOR	P42345	571
RPS6KA3	SLCO6A1	Q86UG4	567
RPS6KA3	RPTOR	Q8N122	565
RPS6KA3	ATF4	P18848	565
RPS6KA3	FGFR1	P11362	560

IntAct

240 interactions, top by confidence:

A	B	Type	Score
RPS6KA3	MAPK1	psi-mi:“MI:0915”(physical association)	0.880
RPS6KA3	MAPK1	psi-mi:“MI:2364”(proximity)	0.880
BCL2L1	BCL2L11	psi-mi:“MI:0914”(association)	0.870
RPS6KA3	CSNK2B	psi-mi:“MI:0915”(physical association)	0.840
FYN	HSP90AA1	psi-mi:“MI:0914”(association)	0.800
RPS6KA1	RPS6KA3	psi-mi:“MI:0914”(association)	0.790
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
MAPK1	MAPK3	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SPRED2	RPS6KA3	psi-mi:“MI:0915”(physical association)	0.670
CSNK2B	RPS6KA5	psi-mi:“MI:0914”(association)	0.660
CSNK2B	NMT2	psi-mi:“MI:0914”(association)	0.660
RPS6KA2	RPS6KA3	psi-mi:“MI:0914”(association)	0.640
RPS6KA3	ROCK2	psi-mi:“MI:0914”(association)	0.640
MAPK1	DHPS	psi-mi:“MI:0914”(association)	0.640
CSNK2B	RPS6KA4	psi-mi:“MI:0914”(association)	0.640
MAPK3	RPS6KA3	psi-mi:“MI:2364”(proximity)	0.610
RPS6KA3	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.590
RPS6KA3	APBA1	psi-mi:“MI:0407”(direct interaction)	0.590
GNAO1	RPS6KA3	psi-mi:“MI:0915”(physical association)	0.560
PIK3R1	RPS6KA3	psi-mi:“MI:0915”(physical association)	0.560
NEK6	RPS6KA3	psi-mi:“MI:0915”(physical association)	0.560
	RPS6KA3	psi-mi:“MI:0915”(physical association)	0.560
PABIR3	RPS6KA3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (295): MAPK1 (Affinity Capture-Western), RPS6KA3 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS), RPS6KA3 (Co-fractionation), RPS6KA3 (Co-fractionation), RPS6KA3 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS), RPS6KA3 (Co-localization), MAPK1 (Co-localization), PDPK1 (Co-localization), RPS6KA3 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1S4CGX4, A9RWC9, A9S5R3, A9SR33, O01775, O14047, O14733, O44408, O80396, P10506, P18652, P18654, P29678, P31938, P36506, P36507, P51812, Q01986, Q02750, Q03428, Q05116, Q08942, Q10664, Q13163, Q18846, Q1HG70, Q20347, Q21307, Q24324, Q4KSH7, Q4V3C8, Q5QN75, Q62862, Q63932, Q63980, Q7TPS0, Q8MXI4, Q91447, Q94A06, Q99JT2

Diamond homologs: A0A509AKL0, A1A4I4, A5K0N4, A7MBL8, A8XJQ6, A8XNJ6, A8XW88, F4HYG2, G1X456, J9W0G9, O42632, O43930, O77676, P00516, P00517, P04409, P05131, P05132, P05383, P05696, P05986, P06244, P06245, P0C605, P10102, P10665, P10666, P11792, P12370, P12688, P16911, P16912, P17252, P17612, P18652, P18654, P18961, P20444, P21137, P22612

SIGNOR signaling

80 interactions.

A	Effect	B	Mechanism
RPS6KA3	“down-regulates activity”	GSK3A	phosphorylation
RPS6KA3	“down-regulates activity”	H3-3A	phosphorylation
RPS6KA3	“down-regulates activity”	H3C1	phosphorylation
RPS6KA3	up-regulates	ATF4	phosphorylation
RPS6KA3	up-regulates	NFATC4	phosphorylation
RPS6KA3	up-regulates	EIF2AK2	phosphorylation
FYN	up-regulates	RPS6KA3	phosphorylation
SRC	up-regulates	RPS6KA3	phosphorylation
SRC	unknown	RPS6KA3	phosphorylation
MAPK1	up-regulates	RPS6KA3	phosphorylation
PDPK1	up-regulates	RPS6KA3	phosphorylation
RPS6KA3	down-regulates	CIC	phosphorylation
RPS6KA3	“up-regulates activity”	KCNK3	phosphorylation
RPS6KA3	unknown	H2BC3	phosphorylation
RPS6KA3	up-regulates	YBX1	phosphorylation
RPS6KA3	up-regulates	ESR1	phosphorylation
MAPK3	up-regulates	RPS6KA3	phosphorylation
RPS6KA3	down-regulates	BAD	phosphorylation
RPS6KA3	unknown	TINF2	phosphorylation
RPS6KA3	up-regulates	WWC1	phosphorylation
SL0101	down-regulates	RPS6KA3	“chemical inhibition”
RPS6KA3	“up-regulates activity”	PFKFB2	phosphorylation
ERK1/2	up-regulates	RPS6KA3	phosphorylation
RPS6KA3	“up-regulates activity”	CREB1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 177 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
ERK/MAPK targets	5	28.5×	3e-05
MAPK targets/ Nuclear events mediated by MAP kinases	5	23.0×	8e-05
Nuclear Events (kinase and transcription factor activation)	6	17.6×	4e-05
MAP kinase activation	6	15.7×	8e-05
Interleukin-17 signaling	7	15.1×	2e-05
Activation of NMDA receptors and postsynaptic events	9	14.1×	3e-06
RHOJ GTPase cycle	8	13.6×	2e-05
Protein-protein interactions at synapses	6	13.5×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
TORC1 signaling	5	25.2×	9e-04
establishment or maintenance of epithelial cell apical/basal polarity	5	18.3×	2e-03
regulation of postsynaptic membrane neurotransmitter receptor levels	5	15.6×	3e-03
establishment of protein localization	5	13.6×	5e-03
Rho protein signal transduction	6	9.3×	6e-03
insulin receptor signaling pathway	6	8.4×	7e-03
protein phosphorylation	17	7.3×	3e-07
MAPK cascade	7	6.7×	7e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — HCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	110
Likely pathogenic	57
Uncertain significance	160
Likely benign	138
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065479	NM_004586.3(RPS6KA3):c.432T>G (p.Tyr144Ter)	Pathogenic
1073446	NC_000023.10:g.(?20204394)(20206108_?)del	Pathogenic
1074355	NM_004586.3(RPS6KA3):c.251del (p.Phe83_Leu84insTer)	Pathogenic
1164016	NM_004586.3(RPS6KA3):c.1152del (p.Phe385fs)	Pathogenic
11650	RPS6KA3, 187-BP DEL, NT406	Pathogenic
11651	NM_004586.3(RPS6KA3):c.224G>T (p.Gly75Val)	Pathogenic
11652	NM_004586.3(RPS6KA3):c.679T>G (p.Ser227Ala)	Pathogenic
11653	NM_004586.3(RPS6KA3):c.244G>T (p.Val82Phe)	Pathogenic
11654	NM_004586.3(RPS6KA3):c.326-1G>C	Pathogenic
11656	NM_004586.3(RPS6KA3):c.451_452del (p.Arg151fs)	Pathogenic
11657	NM_004586.3(RPS6KA3):c.2065C>T (p.Gln689Ter)	Pathogenic
11659	NM_004586.3(RPS6KA3):c.1147C>T (p.Arg383Trp)	Pathogenic
11660	NM_004586.3(RPS6KA3):c.566T>A (p.Ile189Lys)	Pathogenic
11661	NM_004586.3(RPS6KA3):c.486+3A>G	Pathogenic
11663	NM_004586.3(RPS6KA3):c.2144del (p.Ser715fs)	Pathogenic
11664	NM_004586.3(RPS6KA3):c.1000-2A>G	Pathogenic
11665	NG_007488.1:g.67535_67536ins[N[2800];67522_67535]	Pathogenic
11666	NM_004586.3(RPS6KA3):c.803T>C (p.Phe268Ser)	Pathogenic
11667	NM_004586.3(RPS6KA3):c.1428_1430del (p.Ile477del)	Pathogenic
11668	NM_004586.3(RPS6KA3):c.1444_1959dup (p.Val482_Lys653dup)	Pathogenic
1200131	NM_004586.3(RPS6KA3):c.817C>T (p.Arg273Ter)	Pathogenic
1215101	NM_004586.3(RPS6KA3):c.1587T>G (p.Tyr529Ter)	Pathogenic
1323537	NM_004586.3(RPS6KA3):c.1155_1156del (p.Phe385fs)	Pathogenic
1332821	NM_004586.3(RPS6KA3):c.632-2A>C	Pathogenic
1451836	NM_004586.3(RPS6KA3):c.740dup (p.Ser248fs)	Pathogenic
145518	GRCh38/hg38 Xp22.2-22.11(chrX:15173626-23952585)x2	Pathogenic
1455251	NM_004586.3(RPS6KA3):c.770_773del (p.Leu257fs)	Pathogenic
1476999	NM_004586.3(RPS6KA3):c.2142_2145dup (p.Pro716fs)	Pathogenic
155652	GRCh38/hg38 Xp22.12(chrX:20154969-20217590)x0	Pathogenic
1686133	NM_004586.3(RPS6KA3):c.1740del (p.Cys579_Tyr580insTer)	Pathogenic

SpliceAI

3014 predictions. Top by Δscore:

Variant	Effect	Δscore
X:20156103:GCTCA:G	donor_loss	1.0000
X:20156104:CTCAC:C	donor_loss	1.0000
X:20156105:TCACC:T	donor_loss	1.0000
X:20156107:ACCTT:A	donor_loss	1.0000
X:20156108:C:G	donor_loss	1.0000
X:20156108:CCT:C	donor_gain	1.0000
X:20156128:T:TA	donor_gain	1.0000
X:20156245:AGGTC:A	acceptor_gain	1.0000
X:20156246:GGTC:G	acceptor_gain	1.0000
X:20156246:GGTCC:G	acceptor_loss	1.0000
X:20156247:GTC:G	acceptor_gain	1.0000
X:20156248:TC:T	acceptor_gain	1.0000
X:20156248:TCCTG:T	acceptor_loss	1.0000
X:20156249:CC:C	acceptor_gain	1.0000
X:20156249:CCTGT:C	acceptor_loss	1.0000
X:20156250:C:A	acceptor_loss	1.0000
X:20156250:C:CC	acceptor_gain	1.0000
X:20156251:T:C	acceptor_loss	1.0000
X:20161639:CTTA:C	donor_loss	1.0000
X:20161640:TTACC:T	donor_loss	1.0000
X:20161641:TACC:T	donor_loss	1.0000
X:20161642:A:AC	donor_gain	1.0000
X:20161642:AC:A	donor_gain	1.0000
X:20161642:ACCTT:A	donor_loss	1.0000
X:20161643:C:CA	donor_gain	1.0000
X:20161643:CC:C	donor_gain	1.0000
X:20161643:CCT:C	donor_gain	1.0000
X:20161643:CCTTT:C	donor_gain	1.0000
X:20161742:CATT:C	acceptor_gain	1.0000
X:20161757:TGTAA:T	acceptor_gain	1.0000

AlphaMissense

4880 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:20155508:C:G	A705P	1.000
X:20156177:A:G	W678R	1.000
X:20156177:A:T	W678R	1.000
X:20156208:T:A	R667S	1.000
X:20156208:T:G	R667S	1.000
X:20156209:C:G	R667T	1.000
X:20156230:A:G	L660P	1.000
X:20161708:C:G	R632P	1.000
X:20161749:A:C	F618L	1.000
X:20161749:A:T	F618L	1.000
X:20161751:A:G	F618L	1.000
X:20161753:G:T	P617Q	1.000
X:20162991:C:T	G605D	1.000
X:20162992:C:G	G605R	1.000
X:20162996:A:C	S603R	1.000
X:20162996:A:T	S603R	1.000
X:20162998:T:G	S603R	1.000
X:20162999:C:A	W602C	1.000
X:20162999:C:G	W602C	1.000
X:20163001:A:G	W602R	1.000
X:20163001:A:T	W602R	1.000
X:20163006:T:A	D600V	1.000
X:20163006:T:G	D600A	1.000
X:20163007:C:G	D600H	1.000
X:20164939:A:G	L575P	1.000
X:20164971:A:C	F564L	1.000
X:20164971:A:T	F564L	1.000
X:20164973:A:G	F564L	1.000
X:20164980:A:C	D561E	1.000
X:20164980:A:T	D561E	1.000

dbSNP variants (sampled 300 via entrez): RS1000063241 (X:20218945 A>G), RS1000072555 (X:20210215 T>C), RS1000080261 (X:20205406 C>T), RS1000108885 (X:20221070 C>T), RS1000145219 (X:20179842 A>G), RS1000151878 (X:20265960 G>A), RS1000229370 (X:20229473 G>A), RS1000237824 (X:20193730 G>A), RS1000280622 (X:20165291 C>A,G,T), RS1000297887 (X:20154766 G>A), RS1000298690 (X:20220206 A>G), RS1000325108 (X:20230945 A>T), RS1000369735 (X:20175112 G>A,C,T), RS1000370514 (X:20239136 A>T), RS1000387624 (X:20200531 C>G)

Disease associations

OMIM: gene MIM:300075 | disease phenotypes: MIM:303600, MIM:300844, MIM:614429

GenCC curated gene-disease

Disease	Classification	Inheritance
Coffin-Lowry syndrome	Definitive	X-linked
intellectual disability, X-linked 19	Strong	X-linked
symptomatic form of Coffin-Lowry syndrome in female carriers	Supportive	Autosomal dominant
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Coffin-Lowry syndrome	Definitive	XL

Mondo (8): Coffin-Lowry syndrome (MONDO:0010561), intellectual disability, X-linked 19 (MONDO:0010447), intellectual disability (MONDO:0001071), ventricular septal defect (MONDO:0002070), mitral valve prolapse (MONDO:0004910), specific learning disability (MONDO:0016225), symptomatic form of Coffin-Lowry syndrome in female carriers (MONDO:0017193), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (5): Coffin-Lowry syndrome (Orphanet:192), X-linked non-syndromic intellectual disability (Orphanet:777), Specific learning disability (Orphanet:211047), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480)

HPO phenotypes

129 total (30 of 129 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000139	Uterine prolapse
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000189	Narrow palate
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000336	Prominent supraorbital ridges
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000445	Wide nose
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000518	Cataract
HP:0000574	Thick eyebrow
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000674	Anodontia
HP:0000677	Oligodontia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_87	Refractive error	3.000000e-20

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D038921	Coffin-Lowry Syndrome	C10.597.606.360.455.249; C16.320.322.500.249; C16.320.400.525.249
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008945	Mitral Valve Prolapse	C14.280.484.400.500
D000067559	Specific Learning Disorder	C10.597.606.150.550.700; C23.888.592.604.150.550.700; F03.625.374.188.700; F03.625.562.700
C536435	Coffin syndrome 1 (supp.)
C563141	Mental Retardation, X-Linked 19 (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2345 (SINGLE PROTEIN), CHEMBL3832633 (PROTEIN FAMILY), CHEMBL4106179 (PROTEIN FAMILY), CHEMBL4523616 (PROTEIN FAMILY), CHEMBL4630724 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

46 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 194,667 (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
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL3622821	UPADACITINIB	4	2,726
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL38380	FASUDIL	3	11,953
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL483158	ALISERTIB	3	2,305
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1090089	PAMAPIMOD	2	428
CHEMBL1232461	MOLIBRESIB	2	1,538
CHEMBL151	LUTEOLIN	2
CHEMBL1721885	SU-014813	2
CHEMBL1980297	ILORASERTIB	2
CHEMBL1980715	LAUROGUADINE	2
CHEMBL31574	FISETIN	2
CHEMBL362558	LY-2090314	2
CHEMBL4116008	CERDULATINIB	2
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2
CHEMBL521851	PICTILISIB	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — RSK subfamily

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
BIX 02565	Inhibition	8.96	pIC50
compound 8h [PMID: 22765894]	Inhibition	8.52	pIC50
compound 25b [PMID: 22564207]	Inhibition	7.89	pIC50
FMK	Inhibition	7.82	pIC50
BI-D1870	Inhibition	7.62	pIC50

Binding affinities (BindingDB)

189 measured of 222 human assays (222 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(13R)-N-(1-benzylpyrazol-4-yl)-13-methyl-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	0.2 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
14-methyl-10-oxo-N-[1-(pyridin-4-ylmethyl)pyrazol-4-yl]-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	0.27 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(12R,13S)-N-(1-benzylpyrazol-4-yl)-12,13-dimethyl-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	0.34 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(1-benzylpyrazol-4-yl)-14-methyl-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	0.39 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
14-methyl-N-(1-methylpyrazol-4-yl)-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	0.78 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(1-tert-butylpyrazol-4-yl)-14-methyl-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	1.1 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
14-methyl-10-oxo-N-[1-(oxolan-3-ylmethyl)pyrazolo[3,4-b]pyridin-5-yl]-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	1.6 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-[2-(cyclopentylcarbamoyl)-1-methylimidazol-4-yl]-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	1.6 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
Staurosporine	KD	1.7 nM
(E)-2-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-1-cyano-N-propan-2-ylethenesulfonamide	IC50	2 nM	US-9505766: Kinase inhibitors
(R)¿N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide	IC50	2 nM	US-9771366: Substituted tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamides as RSK inhibitors
14-methyl-10-oxo-N-(1-propan-2-ylpyrazolo[3,4-b]pyridin-5-yl)-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	2.1 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(2-carbamoylphenyl)-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	2.3 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
14-methyl-N-[1-(oxan-4-yl)pyrazolo[3,4-b]pyridin-5-yl]-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	2.3 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-cyano-N-cyclopropylprop-2-enamide	IC50	2.4 nM	US-9505766: Kinase inhibitors
(12R,13S)-12,13-dimethyl-N-(5-methyl-1,2-oxazol-3-yl)-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	2.6 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(12S,13S)-N-(1-benzylpyrazol-4-yl)-12,13-dimethyl-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	3 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(13R)-13-methyl-10-oxo-N-quinolin-3-yl-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	3 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-2-cyano-N-(1-hydroxy-2-methylpropan-2-yl)-3-[3-(3,4,5-trimethoxyphenyl)-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-5-yl]prop-2-enamide	IC50	3 nM	US-9505766: Kinase inhibitors
N-(5-benzyl-1,2-oxazol-3-yl)-14-methyl-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	3.3 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(3-benzyl-1,2-oxazol-5-yl)-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	3.6 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-cyano-N-(1,3-dihydroxy-2-methylpropan-2-yl)prop-2-enamide	IC50	3.6 nM	US-9505766: Kinase inhibitors
N-(4-methyl-2-pyridinyl)-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	3.8 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(1-benzylpyrazol-4-yl)-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	3.8 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-cyano-N-(1-hydroxy-2-methylpropan-2-yl)prop-2-enamide	IC50	3.8 nM	US-9505766: Kinase inhibitors
(13R)-N-(5-benzyl-1,2-oxazol-3-yl)-13-methyl-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	3.9 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(13R)-13-methyl-10-oxo-N-(1-propan-2-ylpyrazolo[3,4-b]pyridin-5-yl)-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	4 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
10-oxo-N-(3-phenyl-1,2-oxazol-5-yl)-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	4.3 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-N-tert-butyl-2-cyanoprop-2-enamide	IC50	4.5 nM	US-9505766: Kinase inhibitors
5,5-dimethyl-1-oxo-N-(1-propan-2-ylbenzimidazol-2-yl)-3,4-dihydro-2H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxamide	IC50	4.7 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-(azetidine-1-carbonyl)prop-2-enenitrile	IC50	4.7 nM	US-9505766: Kinase inhibitors
N-(1-methylpyrazol-4-yl)-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	4.8 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-cyano-N’,N’-dimethylprop-2-enehydrazide	IC50	4.8 nM	US-9505766: Kinase inhibitors
(12R,13S)-N-(5-benzyl-1,2-oxazol-3-yl)-12,13-dimethyl-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	5.1 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
14-methyl-N-(5-methyl-1,2-oxazol-3-yl)-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	5.2 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(1-ethylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]benzimidazole-8-carboxamide	IC50	5.5 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(6-chloro-1H-benzimidazol-2-yl)-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	6.1 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-cyano-N,N-dimethylprop-2-enamide	IC50	6.5 nM	US-9505766: Kinase inhibitors
(13R)-13-methyl-N-(5-methyl-1,2-oxazol-3-yl)-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	6.6 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-[6-chloro-4-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	6.7 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
10-oxo-N-quinolin-3-yl-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	9.2 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(1-tert-butylpyrazol-4-yl)-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	9.7 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-(morpholine-4-carbonyl)prop-2-enenitrile	IC50	10.5 nM	US-9505766: Kinase inhibitors
(12R,13S)-N-(1-ethylbenzimidazol-2-yl)-12,13-dimethyl-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	11.6 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(1-benzylpyrazol-4-yl)-13,13-dimethyl-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	12 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(13S)-N-(1-benzylpyrazol-4-yl)-13-methyl-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	IC50	12 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-cyano-N-methoxyprop-2-enamide	IC50	12.6 nM	US-9505766: Kinase inhibitors
10-oxo-N-[1-(oxolan-3-ylmethyl)pyrazolo[3,4-b]pyridin-5-yl]-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	13 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
N-(3-benzyl-1,2-oxazol-5-yl)-14-methyl-10-oxo-1,3,11-triazatricyclo[7.5.0.02,7]tetradeca-2(7),3,5,8-tetraene-4-carboxamide	IC50	13 nM	US-9073926: Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-(3-hydroxyazetidine-1-carbonyl)prop-2-enenitrile	IC50	13.2 nM	US-9505766: Kinase inhibitors

ChEMBL bioactivities

935 potent at pChembl≥5 of 1024 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	IC50	0.0795	nM	STAUROSPORINE
10.07	IC50	0.0855	nM	STAUROSPORINE
9.91	IC50	0.124	nM	STAUROSPORINE
9.80	IC50	0.16	nM	CHEMBL5789687
9.70	IC50	0.2	nM	CHEMBL3673622
9.57	IC50	0.27	nM	CHEMBL3673631
9.52	IC50	0.3	nM	CHEMBL4292020
9.47	IC50	0.34	nM	CHEMBL3673624
9.41	IC50	0.39	nM	CHEMBL3673609
9.27	Kd	0.54	nM	CHEMBL3702836
9.11	IC50	0.78	nM	CHEMBL3673603
9.00	IC50	1	nM	AT-9283
9.00	IC50	1	nM	CHEMBL1933288
9.00	IC50	1	nM	CHEMBL1933280
9.00	Ki	1	nM	CHEMBL1994669
8.96	IC50	1.1	nM	CHEMBL3673606
8.96	IC50	1.1	nM	CHEMBL1933288
8.80	IC50	1.6	nM	CHEMBL2347053
8.80	IC50	1.6	nM	CHEMBL3673598
8.80	IC50	1.6	nM	CHEMBL3639725
8.80	Ki	1.585	nM	CHEMBL1980995
8.77	IC50	1.7	nM	CHEMBL5811142
8.70	IC50	2	nM	CHEMBL4278817
8.70	IC50	2	nM	CHEMBL4289492
8.70	Kd	2	nM	CHEMBL4576489
8.70	IC50	2	nM	CHEMBL1933278
8.70	IC50	2	nM	PF-03758309
8.68	IC50	2.1	nM	CHEMBL3673592
8.64	IC50	2.3	nM	CHEMBL3673589
8.64	IC50	2.3	nM	CHEMBL3673595
8.60	Ki	2.512	nM	GO-6976
8.59	IC50	2.6	nM	CHEMBL3673648
8.52	IC50	3	nM	CHEMBL2086760
8.52	IC50	3	nM	CHEMBL3673625
8.52	IC50	3	nM	CHEMBL3673627
8.48	IC50	3.3	nM	CHEMBL3673657
8.44	IC50	3.6	nM	CHEMBL3673658
8.42	IC50	3.79	nM	CHEMBL3909070
8.42	IC50	3.8	nM	CHEMBL3673601
8.42	IC50	3.8	nM	CHEMBL3673610
8.42	Kd	3.829	nM	CHEMBL3752910
8.41	IC50	3.9	nM	CHEMBL3673661
8.40	IC50	4	nM	CHEMBL2216829
8.40	IC50	4	nM	CHEMBL3604889
8.40	IC50	4	nM	CHEMBL3604794
8.40	IC50	4	nM	CHEMBL3604787
8.40	IC50	4	nM	CHEMBL3604784
8.40	IC50	4	nM	CHEMBL3673629
8.40	Kd	4	nM	CHEMBL4465866
8.40	IC50	4	nM	CHEMBL573107

PubChem BioAssay actives

411 with measured affinity, of 3443 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	1531871: Inhibition of human RSK2 using KKLNRTLSVA as substrate by [gamma-33P]-ATP assay	ic50	0.0001	uM
(13R)-N-(1-benzylpyrazol-4-yl)-13-methyl-10-oxo-1,3,11-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene-4-carboxamide	2008189: Inhibition of RSK2 (unknown origin) preincubated for 1 hr followed by substrate addition and measured after 1 hr by luciferase analysis	ic50	0.0002	uM
2,6-difluoro-4-[4-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenol	1420368: Inhibition of RSK2 (unknown origin)	ic50	0.0003	uM
(E)-2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile	1357759: Binding affinity to RPS6KA3 (unknown origin)	kd	0.0005	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	412604: Inhibition of Rsk2	ic50	0.0010	uM
(5R)-N-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	2008188: Inhibition of human RSK2 in MCF7 cells	ic50	0.0010	uM
N-(1-ethylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0010	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637133: Inhibition of full-length recombinant human His-tagged RPS6KA3 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.0010	uM
(3Z)-3-[[5-(2-nitrophenyl)-1H-pyrazol-4-yl]methylidene]-1H-indol-2-one	739587: Inhibition of RSK2 (unknown origin) using AKRRRLSSLRA as substrate after 60 mins by fluorescence assay	ic50	0.0016	uM
2,6-difluoro-4-[4-(4-morpholin-4-ylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenol	1420368: Inhibition of RSK2 (unknown origin)	ic50	0.0020	uM
2,6-difluoro-4-[4-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenol	1420368: Inhibition of RSK2 (unknown origin)	ic50	0.0020	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	1526310: Binding affinity to recombinant human full length N-terminal GST-tagged RPS6KA3 expressed in baculovirus expression system using S6K peptide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0020	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	2167999: Inhibition of human RSK2 in presence of ATP	ic50	0.0020	uM
1-oxo-N-[1-(pyridin-4-ylmethyl)pyrazol-4-yl]-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	2008188: Inhibition of human RSK2 in MCF7 cells	ic50	0.0020	uM
3-[(4-chlorophenyl)-(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1H-indol-2-one	684382: Inhibition of RSK2	ic50	0.0030	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149311: Binding affinity to human RPS6KA3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0038	uM
2,6-difluoro-4-[4-(4-morpholin-4-ylphenyl)-3-pyridinyl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0040	uM
4-[4-[3-(2-aminoethoxy)phenyl]-3-pyridinyl]-2,6-difluorophenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0040	uM
2,6-difluoro-4-[4-[3-(4-methylpiperazin-1-yl)phenyl]-3-pyridinyl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	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	1526310: Binding affinity to recombinant human full length N-terminal GST-tagged RPS6KA3 expressed in baculovirus expression system using S6K peptide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0040	uM
2-(3,5-difluoro-4-hydroxyanilino)-5,7-dimethyl-8-(3-methylbutyl)-7H-pteridin-6-one	1662138: Inhibition of RSK2 (unknown origin)	ic50	0.0040	uM
(7R)-2-(3,5-difluoro-4-hydroxyanilino)-5,7-dimethyl-8-(3-methylbutyl)-7H-pteridin-6-one	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0040	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	1993902: Inhibition of RSK2 (unknown origin)	ic50	0.0040	uM
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-N-tert-butyl-2-cyanoprop-2-enamide	719883: Inhibition of RSK2 transfected in HEK293 cells	ic50	0.0040	uM
N-(1H-benzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	642313: Inhibition of RSK2 phosphorylation by luminescence assay	ic50	0.0040	uM
N-(3-ethylimidazo[4,5-b]pyridin-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0040	uM
2,6-difluoro-4-[4-[4-(4-methylpiperazin-1-yl)phenyl]-3-pyridinyl]phenol	1781666: Inhibition of full length recombinant His-tagged human RSK2 expressed in baculovirus expression system using biotin-labelled AGAGRSRHSSYPAGT-OH as substrate in presence of ATP	ic50	0.0040	uM
2,6-difluoro-4-[4-[3-(1H-pyrazol-4-yl)phenyl]-3-pyridinyl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0050	uM
(E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-cyano-N-propan-2-ylprop-2-enamide	1469820: Inhibition of RSK2 in human MDA-MB-231 cells after 2 hrs	ic50	0.0050	uM
2,6-difluoro-4-[4-(4-piperazin-1-ylphenyl)-3-pyridinyl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0060	uM
4-[6-amino-4-[4-(4-methylpiperazin-1-yl)phenyl]-3-pyridinyl]-2,6-difluorophenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0060	uM
2,6-difluoro-4-[6-(4-methylanilino)-4-[4-(4-methylpiperazin-1-yl)phenyl]-3-pyridinyl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0060	uM
2,6-difluoro-4-[4-(4-hydroxyphenyl)-1H-pyrazol-5-yl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0060	uM
N-(5-chloro-1-ethylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0060	uM
2,6-difluoro-4-[4-(4-methylphenyl)-3-pyridinyl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0070	uM
tert-butyl (E)-3-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-cyanoprop-2-enoate	1469820: Inhibition of RSK2 in human MDA-MB-231 cells after 2 hrs	ic50	0.0070	uM
N-[1-(cyclohexylmethyl)pyrazol-4-yl]-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0070	uM
2,6-difluoro-4-[4-(4-methoxyphenyl)-3-pyridinyl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0080	uM
N-(1-methylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0090	uM
4-[2-amino-4-(4-methylphenyl)pyrimidin-5-yl]-2,6-difluorophenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0100	uM
3-[3-[4-(1-methylindol-3-yl)-2,5-dioxopyrrol-3-yl]indol-1-yl]propyl carbamimidothioate	1803289: RSK2 Inhibition Assay from Article 10.3109/14756366.2012.681651: “Synthesis, activity evaluation, and docking analysis of barbituric acid aryl hydrazone derivatives as RSK2 inhibitors.”	ic50	0.0100	uM
1-oxo-N-[1-(pyridin-2-ylmethyl)pyrazol-4-yl]-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0100	uM
N-(1-methylpyrazol-4-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0110	uM
N-(6-chloro-1-ethylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0120	uM
N-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	2008188: Inhibition of human RSK2 in MCF7 cells	ic50	0.0120	uM
2,6-difluoro-4-[2-(methylamino)-4-(4-methylphenyl)pyrimidin-5-yl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0130	uM
(1S,2S,3R,4R)-3-[[5-chloro-2-[[(7S)-4-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide	676096: Inhibition of human Rsk2	ic50	0.0130	uM
N-(3-benzyl-1,2-oxazol-5-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0130	uM
2,6-difluoro-4-[6-(methylamino)-4-[4-(4-methylpiperazin-1-yl)phenyl]-3-pyridinyl]phenol	1241242: Inhibition of human recombinant Histidine-tagged RSK2 using biotin-AGAGRSRHSSYPAGT-OH as substrate preincubated for 30 mins followed by ATP and substrate addition measured after 180 mins by AlphaScreen assay	ic50	0.0140	uM
(5S)-N-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	638362: Inhibition of human RSK2	ic50	0.0140	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, affects cotreatment, decreases expression	6
Benzo(a)pyrene	affects methylation, decreases expression	5
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	4
Acetaminophen	decreases expression, increases expression	3
Tretinoin	decreases expression, increases expression, increases phosphorylation, increases reaction	3
Caffeine	affects phosphorylation, decreases expression	2
Valproic Acid	increases expression, increases methylation	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
moringin	affects cotreatment, decreases expression	1
daidzein	increases expression	1
bisphenol A	affects expression	1
tetrahydropalmatine	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
gossypin	affects binding, decreases activity	1
ochratoxin A	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	affects phosphorylation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
7-hydroxystaurosporine	decreases activity	1
tamibarotene	decreases expression	1
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases activity	1

ChEMBL screening assays

770 unique, capped per target: 768 binding, 1 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003317	Binding	Inhibition of RSK2 at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem
CHEMBL1963690	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: RPS6KA3	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

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8NZ	Abcam HCT 116 RPS6KA3 KO	Cancer cell line	Male
CVCL_B9B9	Abcam MCF-7 RPS6KA3 KO	Cancer cell line	Female
CVCL_B9RB	Abcam A-549 RPS6KA3 KO	Cancer cell line	Male
CVCL_D7ZM	Ubigene A-549 RPS6KA3 KO	Cancer cell line	Male
CVCL_E0N1	Ubigene HeLa RPS6KA3 KO	Cancer cell line	Female
CVCL_TJ62	HAP1 RPS6KA3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability