RPS6KA6

Summary

RPS6KA6 (ribosomal protein S6 kinase A6, HGNC:10435) is a protein-coding gene on chromosome Xq21.1, encoding Ribosomal protein S6 kinase alpha-6 (Q9UK32). Constitutively active serine/threonine-protein kinase that exhibits growth-factor-independent kinase activity and that may participate in p53/TP53-dependent cell growth arrest signaling and play an inhibitory role during embryogenesis.

This gene encodes a member of ribosomal S6 kinase family, serine-threonine protein kinases which are regulated by growth factors. The encoded protein may be distinct from other members of this family, however, as studies suggest it is not growth factor dependent and may not participate in the same signaling pathways.

Source: NCBI Gene 27330 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 220 total — 1 pathogenic
• Druggable target: yes — 38 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_014496

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10435
Approved symbol	RPS6KA6
Name	ribosomal protein S6 kinase A6
Location	Xq21.1
Locus type	gene with protein product
Status	Approved
Aliases	RSK4
Ensembl gene	ENSG00000072133
Ensembl biotype	protein_coding
OMIM	300303
Entrez	27330

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000262752, ENST00000460730, ENST00000495332, ENST00000620340, ENST00000699863, ENST00000699864, ENST00000911418, ENST00000911419, ENST00000911420

RefSeq mRNA: 2 — MANE Select: NM_014496 NM_001330512, NM_014496

CCDS: CCDS14451, CCDS83480

Canonical transcript exons

ENST00000262752 — 22 exons

Exon	Start	End
ENSE00000552676	84117384	84117454
ENSE00000552680	84106910	84107040
ENSE00000673163	84135104	84135210
ENSE00000673165	84134782	84134819
ENSE00000673190	84116229	84116287
ENSE00000673194	84106365	84106487
ENSE00000673196	84104499	84104657
ENSE00000673197	84102037	84102198
ENSE00000847170	84058350	84064402
ENSE00000847171	84064971	84065111
ENSE00001169610	84187819	84188199
ENSE00001614546	84148042	84148123
ENSE00001659155	84107623	84107725
ENSE00001702802	84146978	84147058
ENSE00001719694	84117060	84117148
ENSE00001783794	84119885	84120027
ENSE00001800735	84145478	84145557
ENSE00003552600	84105787	84105876
ENSE00003565820	84156075	84156191
ENSE00003661040	84096194	84096311
ENSE00003662194	84164328	84164387
ENSE00003680268	84097772	84097848

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 97.35.

FANTOM5 (CAGE): breadth broad, TPM avg 3.0793 / max 1738.9292, expressed in 813 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199857	1.1480	73
199860	0.8512	445
199859	0.6082	307
209747	0.3017	163
199858	0.1702	85

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.35	gold quality
secondary oocyte	CL:0000655	82.68	gold quality
oocyte	CL:0000023	79.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.42	gold quality
cartilage tissue	UBERON:0002418	78.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.13	gold quality
tibia	UBERON:0000979	77.51	gold quality
cortical plate	UBERON:0005343	76.87	gold quality
islet of Langerhans	UBERON:0000006	76.43	gold quality
embryo	UBERON:0000922	75.16	gold quality
ganglionic eminence	UBERON:0004023	75.16	gold quality
ventricular zone	UBERON:0003053	75.11	gold quality
oviduct epithelium	UBERON:0004804	75.00	gold quality
middle temporal gyrus	UBERON:0002771	74.75	gold quality
pituitary gland	UBERON:0000007	74.72	gold quality
popliteal artery	UBERON:0002250	74.39	gold quality
tibial artery	UBERON:0007610	74.39	gold quality
descending thoracic aorta	UBERON:0002345	74.20	gold quality
adenohypophysis	UBERON:0002196	73.91	gold quality
epithelial cell of pancreas	CL:0000083	73.82	gold quality
aorta	UBERON:0000947	73.69	gold quality
thyroid gland	UBERON:0002046	73.61	gold quality
seminal vesicle	UBERON:0000998	73.39	gold quality
left lobe of thyroid gland	UBERON:0001120	73.12	gold quality
thoracic aorta	UBERON:0001515	72.89	gold quality
ascending aorta	UBERON:0001496	72.74	gold quality
colonic mucosa	UBERON:0000317	72.73	gold quality
mucosa of sigmoid colon	UBERON:0004993	72.61	gold quality
corpus epididymis	UBERON:0004359	72.60	gold quality
bronchial epithelial cell	CL:0002328	72.26	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-106540	no	15.69
E-ANND-3	no	5.36
E-MTAB-6379	no	2.52
E-MTAB-4850	no	0.53

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A, MYC

miRNA regulators (miRDB)

393 targeting RPS6KA6, 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-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996

Literature-anchored findings (GeneRIF, showing 28)

• The unusual regulation and growth factor-independent activity of ribosomal S6 kinase 4 (RSK4) indicate that it is functionally distinct from other RSKs and may explain why RSK4 can participate in non-growth factor signaling. (PMID:15632195)
• Downregulation of RPS6KA6 is associated with colon carcinoma. (PMID:16865262)
• RT-PCR data show high expression of putative tumor suppressor genes Rsk4 and RbAp46 in 47% and 79% of breast carcinoma cases, respectively, whereas Cldn2 was down-regulated in 52% of breast cancer cases compared with normal adjacent tissues. (PMID:17314274)
• RSK4 expression may limit the oncogenic, invasive, and metastatic potential of breast cancer cells. (PMID:18628456)
• Results support the concept that RSK4 may be an important tumor suppressor gene by modulating senescence induction and contributing to cell proliferation control in colon carcinogenesis and renal cell carcinomas. (PMID:19584160)
• importance of RSK4 for regulating senescence and indicate that downregulation of this kinase could be an important element in facilitating cell transformation. (PMID:21239520)
• Data indicate that RSK4 appears to be epigenetically silenced in endometrial cancer as evidenced by hypermethylation. (PMID:21372219)
• A total of six novel and 11 known single nucleotide polymorphisms were identified. Further studies are warranted to analyze the candidate genes at Xq11.1-q21.33. (PMID:21384559)
• The expression level of RSK-4 mRNA in breast cancer was significantly lower than those in normal breast tissues and breast benign lesions tissues. The down-regulation of RSK-4 expression in breast caner suggests that it is a breast cancer suppressor gene. (PMID:21875487)
• findings reveals a major role of PRKX, TTBK2 and RSK4 in triggering Sunitinib resistance formation; data suggest transcriptional regulation of these kinases together with other proteins might play an important role in formation of Sunitinib resistance by affecting transcription factors (PMID:22020623)
• Suggest that RSK4 may serve as a mediator of endothelial progenitor cell senescence in diabetes mellitus. (PMID:22297070)
• Overexpression of RSK3 or RSK4 supports tumor cell proliferation upon PI3K inhibition both in vitro and in vivo therby contributing to drug resistance. (PMID:23635776)
• evaluated expression of RSK4 in renal cell carcinoma(RCC)tissues, analysed relationship between RSK4 expression and clinicopathological features of RCC patients and explored potential molecular mechanisms of RSK4 in RCC cell lines; expression pattern and molecular mechanisms of RSK4 in RCCs indicate it could be a potential independent prognostic factor (PMID:23942078)
• RSK4 mRNA is significantly decreased in most of breast cancer tissues compared with paired non-cancerous tissues, due to promoter hypermethylation; frequent epigenetic inactivation might have a role in precancerous lesions or early cancer (PMID:24338215)
• Low RSK4 expression is correlated with advanced clinical pathologic classifications and is a poor overall survival in colorectal cancer patients (PMID:25197367)
• downregulation of RSK4 expression is indicated to be associated with tumor cell proliferation and invasion, and silencing of the RSK4 may be involved in the development and progression of breast cancer (PMID:26397146)
• RSK4 is expressed at low levels in malignant ovarian tumors, which correlates with advanced stages of the disease. (PMID:26732474)
• The regulatory role of RSK4 in breast cancer development was mediated by AKT and extracellular signalregulated kinase (ERK) signaling pathways and the expression of RSK4 was altered by DNA methylation in promoter regions. (PMID:28731146)
• RSK4 constitutes a putative tumor suppressor gene for non-small cell lung carcinoma. (PMID:30143490)
• High expression of RSK4 is associated with colorectal cancer. (PMID:30579335)
• E2 signaling may therefore act upstream of RSK4 to promote cancer progression. The results obtained in the current study suggested that RSK4 inhibited breast cancer cell invasiveness and that RSK4 promoter hypomethylation may serve as a novel prognostic marker for patients with breast cancer. (PMID:31545499)
• Overexpression of RSK4 reverses doxorubicin resistance in human breast cancer cells via PI3K/AKT signalling pathway. (PMID:31960922)
• Hypermethylation of the RSK4 promoter associated with BRAF V600E promotes papillary thyroid carcinoma. (PMID:32319586)
• Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma. (PMID:32396532)
• RSK4: a new prognostic factor in glioma. (PMID:32703488)
• High RSK4 expression constitutes a predictor of poor prognosis for patients with clear cell renal carcinoma. (PMID:34649054)
• Ribosomal S6 kinase 4 (RSK4) tumor suppressor gene promoter methylation status in ovarian cancer. (PMID:37402066)
• RSK4 promotes the macrophage recruitment and M2 polarization in esophageal squamous cell carcinoma. (PMID:38142759)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	rps6kal	ENSDARG00000037574
mus_musculus	Rps6ka6	ENSMUSG00000025665
rattus_norvegicus	Rps6ka6	ENSRNOG00000002592
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), RPS6KA5 (ENSG00000100784), RPS6KB1 (ENSG00000108443), RPS6KA1 (ENSG00000117676), RPS6KA4 (ENSG00000162302), RPS6KB2 (ENSG00000175634), RPS6KA3 (ENSG00000177189)

Protein

Protein identifiers

Ribosomal protein S6 kinase alpha-6 — Q9UK32 (reviewed: Q9UK32)

Alternative names: 90 kDa ribosomal protein S6 kinase 6, Ribosomal S6 kinase 4, pp90RSK4

All UniProt accessions (4): Q9UK32, A0AAU7BN28, A0AAU7BN44, A0AAU7BNA2

UniProt curated annotations — full annotation on UniProt →

Function. Constitutively active serine/threonine-protein kinase that exhibits growth-factor-independent kinase activity and that may participate in p53/TP53-dependent cell growth arrest signaling and play an inhibitory role during embryogenesis.

Subunit / interactions. Forms a complex with MAPK3/ERK1 but not with MAPK9 or MAPK14 in serum-starved cells.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Post-translational modifications. Phosphorylated at Ser-232, Ser-372, and Ser-389 in serum-starved cells.

Activity regulation. Constitutively activated by phosphorylation at Ser-232, Ser-372, and Ser-389 in serum-starved cells. Does not require growth factor stimulation for significant kinase activity.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UK32-1	1	yes
Q9UK32-2	2

RefSeq proteins (2): NP_001317441, NP_055311* (*=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
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 (52 total): helix 14, strand 10, binding site 4, modified residue 4, domain 3, sequence variant 3, mutagenesis site 3, sequence conflict 3, turn 3, active site 2, chain 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6G77	X-RAY DIFFRACTION	2.5
6G78	X-RAY DIFFRACTION	2.5
6G76	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UK32-F1	74.68	0.31

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): 198 (proton acceptor); 543 (proton acceptor)

Ligand- & substrate-binding residues (4): 455; 79–87; 105; 432–440

Post-translational modifications (4): 232, 372, 389, 581

Mutagenesis-validated functional residues (3):

Position	Phenotype
372	no effect on activity.
389	strongly decreases activity.
581	no effect on activity.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
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-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-373760	L1CAM interactions
R-HSA-422475	Axon guidance
R-HSA-438064	Post NMDA receptor activation events
R-HSA-442755	Activation of NMDA receptors and postsynaptic events
R-HSA-9675108	Nervous system development

MSigDB gene sets: 210 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, BENPORATH_ES_WITH_H3K27ME3, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_REGULATION_OF_MESODERM_DEVELOPMENT, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_DNA_DAMAGE_RESPONSE, GOBP_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_TOR_SIGNALING, GOBP_SIGNAL_TRANSDUCTION_IN_RESPONSE_TO_DNA_DAMAGE, GOBP_EMBRYO_DEVELOPMENT

GO Biological Process (9): signal transduction (GO:0007165), central nervous system development (GO:0007417), DNA damage response, signal transduction by p53 class mediator (GO:0030330), TORC1 signaling (GO:0038202), negative regulation of embryonic development (GO:0045992), negative regulation of ERK1 and ERK2 cascade (GO:0070373), negative regulation of mesoderm development (GO:2000381), protein phosphorylation (GO:0006468), intracellular signal transduction (GO:0035556)

GO Molecular Function (11): magnesium ion binding (GO:0000287), protein kinase activity (GO:0004672), ribosomal protein S6 kinase activity (GO:0004711), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein serine/threonine kinase activity (GO:0004674), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): fibrillar center (GO:0001650), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
L1CAM interactions	1
Post NMDA receptor activation events	1
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1
Transmission across Chemical Synapses	1
Neuronal System	1
Axon guidance	1
Nervous system development	1
Activation of NMDA receptors and postsynaptic events	1
Neurotransmitter receptors and postsynaptic signal transmission	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
negative regulation of developmental process	2
intracellular anatomical structure	2
protein kinase activity	2
nuclear lumen	2
cytoplasm	2
intracellular membrane-bounded organelle	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
nervous system development	1
system development	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
TOR signaling	1
embryo development	1
regulation of embryonic development	1
negative regulation of multicellular organismal process	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
mesoderm development	1
regulation of mesoderm development	1
phosphorylation	1
protein modification process	1
signal transduction	1
metal ion binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1

Protein interactions and networks

STRING

936 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPS6KA6	OPHN1	O60890	788
RPS6KA6	ATRX	P46100	596
RPS6KA6	SATL1	Q86VE3	495
RPS6KA6	CYLC1	P35663	470
RPS6KA6	IGF1	P01343	469
RPS6KA6	SH3BGRL	O75368	459
RPS6KA6	TMEM150A	Q86TG1	445
RPS6KA6	APOOL	Q6UXV4	439
RPS6KA6	RPS6KA1	Q15418	423
RPS6KA6	ZNF711	Q9Y462	389
RPS6KA6	IQSEC2	Q5JU85	384
RPS6KA6	BBOF1	Q8ND07	380
RPS6KA6	FRMD4A	Q9P2Q2	375
RPS6KA6	HSPH1	Q92598	372
RPS6KA6	GPR160	Q9UJ42	344

IntAct

43 interactions, top by confidence:

A	B	Type	Score
CSNK2B	NMT2	psi-mi:“MI:0914”(association)	0.660
SPRED2	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.560
MAPK3	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.550
OSGIN1	BTBD1	psi-mi:“MI:0914”(association)	0.530
HSP90AB1	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.400
RPS6KA6	ADIRF	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	ERG28	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	SYNE4	psi-mi:“MI:0915”(physical association)	0.370
CEBPZ	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	CENPB	psi-mi:“MI:0915”(physical association)	0.370
CLEC3B	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
DHX34	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	DNAJC13	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	DNMT1	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	FBN3	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	LMO4	psi-mi:“MI:0915”(physical association)	0.370
MASP1	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	MED24	psi-mi:“MI:0915”(physical association)	0.370
MICAL1	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
MPP1	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	RBPJ	psi-mi:“MI:0915”(physical association)	0.370
RPLP1	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	RXRA	psi-mi:“MI:0915”(physical association)	0.370
SAP30BP	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	SPTBN4	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	UFM1	psi-mi:“MI:0915”(physical association)	0.370
ZNF227	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	ZNF746	psi-mi:“MI:0915”(physical association)	0.370
FZD5	RPS6KA6	psi-mi:“MI:0915”(physical association)	0.370
	SGK1	psi-mi:“MI:0914”(association)	0.350

BioGRID (83): RPS6KA6 (Affinity Capture-MS), RPS6KA6 (Affinity Capture-MS), RPS6KA6 (Affinity Capture-MS), GGA2 (Proximity Label-MS), LTN1 (Proximity Label-MS), MAPK1 (Proximity Label-MS), MAPK3 (Proximity Label-MS), GRSF1 (Proximity Label-MS), FLOT2 (Proximity Label-MS), RGPD1 (Proximity Label-MS), DLAT (Proximity Label-MS), SMN2 (Proximity Label-MS), TRIM33 (Proximity Label-MS), NR4A1 (Two-hybrid), SPRED2 (Two-hybrid)

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

3 interactions.

A	Effect	B	Mechanism
RPS6KA6	“down-regulates activity”	EP300	phosphorylation
RPS6KA6	“up-regulates activity”	RPS6KA6	phosphorylation
RPS6KA6	“down-regulates activity”	GSK3B	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
Diseases of signal transduction by growth factor receptors and second messengers	5	8.6×	7e-03
Signaling by Receptor Tyrosine Kinases	5	7.8×	7e-03
Hemostasis	6	6.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	39
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
833505	NC_000023.10:g.(?82763333)(86890775_?)del	Pathogenic

SpliceAI

3241 predictions. Top by Δscore:

Variant	Effect	Δscore
X:84096188:TTATA:T	donor_loss	1.0000
X:84096189:TATAC:T	donor_loss	1.0000
X:84096191:TACCT:T	donor_loss	1.0000
X:84096193:C:CT	donor_loss	1.0000
X:84096292:C:CT	acceptor_gain	1.0000
X:84096307:TGTAG:T	acceptor_gain	1.0000
X:84096308:GTAG:G	acceptor_gain	1.0000
X:84096309:TAG:T	acceptor_gain	1.0000
X:84096310:AG:A	acceptor_gain	1.0000
X:84096311:GCTA:G	acceptor_loss	1.0000
X:84096312:C:CC	acceptor_gain	1.0000
X:84096312:C:CG	acceptor_loss	1.0000
X:84104497:A:AC	donor_gain	1.0000
X:84104497:ACT:A	donor_gain	1.0000
X:84104497:ACTC:A	donor_gain	1.0000
X:84104498:C:CC	donor_gain	1.0000
X:84104498:CT:C	donor_gain	1.0000
X:84104498:CTC:C	donor_gain	1.0000
X:84104498:CTCC:C	donor_gain	1.0000
X:84104529:A:AC	donor_gain	1.0000
X:84104530:C:CC	donor_gain	1.0000
X:84105759:G:C	donor_gain	1.0000
X:84105783:CTA:C	donor_loss	1.0000
X:84105785:A:AC	donor_gain	1.0000
X:84105785:AC:A	donor_loss	1.0000
X:84105785:ACAT:A	donor_gain	1.0000
X:84105785:ACATC:A	donor_gain	1.0000
X:84105786:C:CC	donor_gain	1.0000
X:84105786:CAT:C	donor_gain	1.0000
X:84105786:CATC:C	donor_gain	1.0000

AlphaMissense

4924 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:84102119:T:A	D565V	1.000
X:84102119:T:G	D565A	1.000
X:84102188:C:G	R542P	1.000
X:84104626:A:T	V496D	1.000
X:84106365:C:A	K455N	1.000
X:84106365:C:G	K455N	1.000
X:84106988:G:C	F388L	1.000
X:84106988:G:T	F388L	1.000
X:84106989:A:G	F388S	1.000
X:84106990:A:G	F388L	1.000
X:84106997:G:C	F385L	1.000
X:84106997:G:T	F385L	1.000
X:84106998:A:G	F385S	1.000
X:84106999:A:G	F385L	1.000
X:84107642:A:C	F364L	1.000
X:84107642:A:T	F364L	1.000
X:84107644:A:G	F364L	1.000
X:84107654:A:C	F360L	1.000
X:84107654:A:T	F360L	1.000
X:84107656:A:G	F360L	1.000
X:84117064:T:A	R315S	1.000
X:84117064:T:G	R315S	1.000
X:84117065:C:G	R315T	1.000
X:84117066:T:C	R315G	1.000
X:84117079:C:A	R310S	1.000
X:84117079:C:G	R310S	1.000
X:84117080:C:A	R310M	1.000
X:84117390:A:T	I285K	1.000
X:84117425:A:C	F273L	1.000
X:84117425:A:T	F273L	1.000

dbSNP variants (sampled 300 via entrez): RS1000054503 (X:84176264 C>T), RS1000055760 (X:84183915 G>A), RS1000191431 (X:84088845 G>A), RS1000198308 (X:84140265 G>A), RS1000208123 (X:84183548 A>G), RS1000219065 (X:84073880 G>A,T), RS1000235615 (X:84121574 C>A), RS1000350432 (X:84060803 G>A,T), RS1000369611 (X:84167191 C>T), RS1000399605 (X:84096863 A>G), RS1000414342 (X:84120983 G>A), RS1000414741 (X:84088557 G>A,T), RS1000431121 (X:84149230 T>G), RS1000460098 (X:84158315 C>T), RS1000506204 (X:84121263 T>C)

Disease associations

OMIM: gene MIM:300303 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3832633 (PROTEIN FAMILY), CHEMBL4630724 (PROTEIN FAMILY), CHEMBL4924 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

38 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 322,462 (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
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL2103743	TOFACITINIB CITRATE	4	1,672
CHEMBL221959	TOFACITINIB	4	10,408
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL1721885	SU-014813	2	363
CHEMBL230011	TG100-115	2
CHEMBL2386889	SCH-900776	2
CHEMBL4116008	CERDULATINIB	2
CHEMBL495727	AT-9283	2
CHEMBL513909	BI-2536	2
CHEMBL521851	PICTILISIB	2
CHEMBL565612	SOTRASTAURIN	2
CHEMBL574737	UCN-01	2
CHEMBL3544960	AT-13148	1
CHEMBL1908394	GSK-461364	1

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
AT-9283	Inhibition	8.0	pIC50
BI-D1870	Inhibition	7.82	pIC50
compound 25b [PMID: 22564207]	Inhibition	7.72	pIC50
BAY-985	Inhibition	6.56	pIC50
compound 39 [PMID: 40643363]	Inhibition	5.53	pIC50

Binding affinities (BindingDB)

39 measured of 39 human assays (39 total across all organisms); most potent 39 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 nM
(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
3-[(1-benzyltetrazol-5-yl)-(2,3-dihydroindol-1-yl)methyl]-7-methyl-1H-quinolin-2-one	IC50	6 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole	KD	9.8 nM
US20250388576, Compound 005-1	IC50	11 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
4-[4-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazol-5-yl]pyridine	KD	12 nM
N-(4-butoxyphenyl)-4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]piperidine-1-carboxamide	IC50	12 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
US20250388576, Compound 017	IC50	12 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
[1,2,5-trimethyl-4-(3-methylphenyl)piperidin-4-yl] propanoate	IC50	13 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
N-(3-fluoro-4-methylphenyl)-4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]piperidine-1-carboxamide	IC50	14 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]-N-(2-phenylethyl)piperidine-1-carboxamide	IC50	17 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
(R)-1-benzyl-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3’,2’:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide	IC50	23.6 nM	US-9771366: Substituted tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamides as RSK inhibitors
N-[2-(dimethylamino)-2-phenylethyl]-3-(3-methylphenoxy)propanamide	IC50	30 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
ethyl 6-[[4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]piperidine-1-carbonyl]amino]hexanoate	IC50	39 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
N-ethyl-4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]piperidine-1-carboxamide	IC50	39 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]-N-pentylpiperidine-1-carboxamide	IC50	44 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
1-[1-[(2,5-dimethylphenyl)methyl]piperidin-4-yl]-5-fluorobenzotriazole	IC50	46 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]-N-[4-(trifluoromethyl)phenyl]piperidine-1-carboxamide	IC50	57 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
1-cyclohexyl-3-[2-(dimethylamino)-2-pyridin-3-ylethyl]urea	IC50	86 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
methyl 2-[[4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]piperidine-1-carbonyl]amino]benzoate	IC50	131 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
N-(3,5-dimethylphenyl)-4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]piperidine-1-carboxamide	IC50	139 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]-N-propan-2-ylpiperidine-1-carboxamide	IC50	180 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
PKC-412	KD	190 nM
N-[1-(4-phenylpiperazin-1-yl)-1-thiophen-2-ylpropan-2-yl]butanamide	IC50	201 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
3-[(1-benzyltetrazol-5-yl)-(4-methylpiperazin-1-yl)methyl]-8-methyl-1H-quinolin-2-one	IC50	214 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]-N-propylpiperidine-1-carboxamide	IC50	280 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
2-[(3,5-difluoro-4-hydroxyphenyl)amino]-5,7-dimethyl-8-(3-methylbutyl)-5,6,7,8-tetrahydropteridin-6-one	IC50	340 nM
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide	KD	370 nM
1-[[2-(3,4-dimethoxyphenyl)-5-methyl-1,3-oxazol-4-yl]methyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-carboxamide	IC50	392 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
(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
N-(3-acetylphenyl)-4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]piperidine-1-carboxamide	IC50	3020 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF
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
3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile	KD	5000 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM
4-[3-[4-(6-methyl-2-pyridinyl)piperazine-1-carbonyl]piperidin-1-yl]-N-(2,4,4-trimethylpentan-2-yl)piperidine-1-carboxamide	IC50	10800 nM	US-20250388576: PYRIDONOPYRIMIDINE DERIVATIVE AS RSK INHIBITOR AND USE THEREOF

ChEMBL bioactivities

152 potent at pChembl≥5 of 161 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.99	IC50	0.102	nM	STAUROSPORINE
9.87	IC50	0.134	nM	STAUROSPORINE
9.80	IC50	0.159	nM	STAUROSPORINE
9.52	IC50	0.3	nM	CHEMBL5811142
8.42	IC50	3.79	nM	CHEMBL3909070
8.40	Kd	4	nM	PF-03758309
8.40	IC50	4	nM	CERDULATINIB
8.36	IC50	4.37	nM	CHEMBL573107
8.15	IC50	7	nM	CHEMBL4543618
8.12	IC50	7.58	nM	CHEMBL3927587
8.10	IC50	8	nM	CHEMBL5816107
8.10	IC50	8	nM	CHEMBL5786213
8.02	IC50	9.5	nM	CHEMBL4847762
8.00	IC50	10	nM	CHEMBL573107
7.99	IC50	10.3	nM	CHEMBL3924878
7.94	IC50	11.5	nM	CHEMBL573107
7.92	IC50	12	nM	AT-13148
7.92	IC50	12	nM	CHEMBL4847469
7.92	IC50	12	nM	CHEMBL4846725
7.90	IC50	12.7	nM	CHEMBL3911801
7.85	Kd	14	nM	CHEMBL4576489
7.82	IC50	15	nM	CHEMBL573107
7.82	IC50	15	nM	CHEMBL4870231
7.81	IC50	15.5	nM	CHEMBL4870807
7.80	Kd	16	nM	AT-9283
7.75	IC50	18	nM	CHEMBL4846978
7.75	Kd	18	nM	STAUROSPORINE
7.72	IC50	19	nM	CHEMBL2064666
7.68	Kd	21	nM	CHEMBL4465866
7.60	IC50	25	nM	CHEMBL4845942
7.60	Kd	25	nM	ENZASTAURIN
7.57	Kd	27	nM	TAE-684
7.54	IC50	28.5	nM	CHEMBL4872665
7.53	IC50	29.4	nM	CHEMBL3889534
7.48	IC50	33	nM	CHEMBL4852908
7.44	IC50	36	nM	BAY-3827
7.43	IC50	37	nM	CHEMBL5086263
7.38	IC50	42	nM	BRIGATINIB
7.26	IC50	54.9	nM	CHEMBL4850890
7.24	Kd	57	nM	CHEMBL3688339
7.17	IC50	66.82	nM	CHEMBL5423601
7.08	IC50	84	nM	CHEMBL4856762
7.04	IC50	91.28	nM	CHEMBL6193190
7.00	Ki	100	nM	CHEMBL4249925
6.96	Kd	110	nM	LESTAURTINIB
6.93	IC50	117	nM	CHEMBL4869608
6.85	Kd	141	nM	UCN-01
6.82	Kd	150	nM	RUXOLITINIB
6.80	Kd	160	nM	TAE-684
6.77	IC50	170	nM	CHEMBL4538751

PubChem BioAssay actives

133 with measured affinity, of 1165 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	1715177: Inhibition of human RSK4 using KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK as substrate by [gamma-33P]-ATP assay	ic50	0.0001	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	1425163: 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	0.0040	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	1993903: Inhibition of RSK4 (unknown origin)	ic50	0.0040	uM
3,3,3-trifluoro-1-[4-[(1R)-1-[2-[[6-(5-propan-2-yloxypyrimidin-4-yl)-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]propan-1-one	1582168: Inhibition of recombinant full length human His6-tagged RSK4 expressed in baculovirus infected sf21 cells using biotin labelled Ahx-KKLNRTLSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.0070	uM
1-cyclopentyl-7-(3,5-difluoro-4-hydroxyanilino)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0095	uM
2-(3,5-difluoro-4-hydroxyanilino)-5,7-dimethyl-8-(3-methylbutyl)-7H-pteridin-6-one	2077315: Inhibition of RSK4 (14 to 702 residues) (unknown origin) using KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK peptide as substrate incubated for 10 mins in presence of [gamma-32p]ATP	ic50	0.0100	uM
1-cyclopentyl-7-(3,5-difluoro-4-hydroxyanilino)-4-pentan-3-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0120	uM
1-cyclohexyl-7-(3,5-difluoro-4-hydroxyanilino)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0120	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	1526287: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged RPS6KA6 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0140	uM
7-(3,5-difluoro-4-hydroxyanilino)-1-(3-methylcyclohexyl)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0150	uM
7-(3,5-difluoro-4-hydroxyanilino)-1-(3-methylbutyl)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0155	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1425163: 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	0.0160	uM
1-cyclopentyl-7-(3-fluoro-4-hydroxyanilino)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0180	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	676098: Inhibition of human Rsk4	ic50	0.0190	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	1526287: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged RPS6KA6 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0210	uM
1-cyclobutyl-7-(3,5-difluoro-4-hydroxyanilino)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0250	uM
3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione	625081: Binding constant for RSK4(Kin.Dom.1-N-terminal) kinase domain	kd	0.0250	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	625081: Binding constant for RSK4(Kin.Dom.1-N-terminal) kinase domain	kd	0.0270	uM
7-(3,5-difluoro-4-hydroxyanilino)-1-(4-methylcyclohexyl)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0285	uM
7-(3-chloro-4-hydroxyanilino)-1-cyclopentyl-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0330	uM
22-fluoro-10,14-dimethyl-9-oxo-3-(trifluoromethyl)-4,5,10,13,14,19,21-heptazapentacyclo[15.5.2.12,5.012,16.020,23]pentacosa-1(22),2(25),3,12,15,17(24),18,20(23)-octaene-15-carbonitrile	1823467: Inhibition of RSK4 (unknown origin) at 1 uM by kinome scan method	ic50	0.0370	uM
Brigatinib	2182817: Inhibition of human RPS6KA6 using KKLNRTLSVA as substrate in presence of [gamma33P]-ATP by HotSpot assay	ic50	0.0420	uM
7-(3,5-difluoro-4-hydroxyanilino)-1-(oxolan-3-yl)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0549	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425163: 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	0.0570	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
7-(4-hydroxyanilino)-1-(3-methylbutyl)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.0840	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
(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	508080: Binding affinity to RPS6KA6(Kin.Dom.1-N-terminal)	kd	0.1100	uM
N-[3-[7-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-4,4-dimethyl-2-oxopyrimido[4,5-d][1,3]oxazin-1-yl]phenyl]prop-2-enamide	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.1170	uM
(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1425163: 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	0.1410	uM
Ruxolitinib	625082: Binding constant for RSK4(Kin.Dom.2-C-terminal) kinase domain	kd	0.1500	uM
3,3,3-trifluoro-1-[4-[(1R)-1-[2-[[6-(6-methylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]propan-1-one	1582168: Inhibition of recombinant full length human His6-tagged RSK4 expressed in baculovirus infected sf21 cells using biotin labelled Ahx-KKLNRTLSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.1700	uM
3,3,3-trifluoro-1-[4-[[2-[[6-[6-(methylamino)pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]methyl]piperazin-1-yl]propan-1-one	1582168: Inhibition of recombinant full length human His6-tagged RSK4 expressed in baculovirus infected sf21 cells using biotin labelled Ahx-KKLNRTLSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.1770	uM
3,3,3-trifluoro-1-[4-[(1R)-1-[2-[[6-[6-(methoxymethyl)pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]propan-1-one	1582168: Inhibition of recombinant full length human His6-tagged RSK4 expressed in baculovirus infected sf21 cells using biotin labelled Ahx-KKLNRTLSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.1920	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625081: Binding constant for RSK4(Kin.Dom.1-N-terminal) kinase domain	kd	0.2300	uM
Vandetanib	435194: Binding constant for RPS6KA6(Kin.Dom.2 - N-terminal) kinase domain	kd	0.2400	uM
4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine	435194: Binding constant for RPS6KA6(Kin.Dom.2 - N-terminal) kinase domain	kd	0.2500	uM
4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]phenol	435194: Binding constant for RPS6KA6(Kin.Dom.2 - N-terminal) kinase domain	kd	0.2700	uM
1-[4-[(1R)-1-[2-[[6-[6-(dimethylamino)pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	1582168: Inhibition of recombinant full length human His6-tagged RSK4 expressed in baculovirus infected sf21 cells using biotin labelled Ahx-KKLNRTLSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.2760	uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione	1425163: 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	0.2760	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	1425163: 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	0.2820	uM
1-cyclopentyl-7-[4-(4-methylpiperazin-1-yl)anilino]-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.3005	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149314: Binding affinity to human RPS6KA6 incubated for 45 mins by Kinobead based pull down assay	kd	0.3101	uM
1-[4-[(1R)-1-[2-[[6-[1-(cyclobutylmethyl)pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	1582168: Inhibition of recombinant full length human His6-tagged RSK4 expressed in baculovirus infected sf21 cells using biotin labelled Ahx-KKLNRTLSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.3250	uM
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide	625081: Binding constant for RSK4(Kin.Dom.1-N-terminal) kinase domain	kd	0.3500	uM
Fedratinib	625082: Binding constant for RSK4(Kin.Dom.2-C-terminal) kinase domain	kd	0.3600	uM
3-[7-(3,5-difluoro-4-hydroxyanilino)-2-oxo-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-1-yl]-N-methylbenzamide	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.3950	uM
1-cyclopentyl-7-(4-piperazin-1-ylanilino)-4-propan-2-yl-4H-pyrimido[4,5-d][1,3]oxazin-2-one	1781669: Inhibition of RSK4 (unknown origin) incubated for 40 mins in presence of ATP and lipid substrate by Kinase-Glo plus luminescence assay	ic50	0.4100	uM
Midostaurin	1425163: 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	0.4190	uM
3,3,3-trifluoro-1-[4-[[2-[[6-(6-methylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino]-4-pyridinyl]methyl]piperazin-1-yl]propan-1-one	1582168: Inhibition of recombinant full length human His6-tagged RSK4 expressed in baculovirus infected sf21 cells using biotin labelled Ahx-KKLNRTLSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.4340	uM

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Nickel	decreases expression	2
methylmercuric chloride	decreases expression	1
afimoxifene	decreases expression, decreases reaction	1
sodium arsenite	decreases expression	1
aflatoxin B2	increases methylation	1
avobenzone	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1
Estrogens	decreases expression, decreases reaction	1
Tetrachlorodibenzodioxin	decreases expression	1
Zinc Sulfate	increases expression	1

ChEMBL screening assays

353 unique, capped per target: 352 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3734183	Binding	Inhibition of RPS6 kinase phosphorylation in cells (unknown origin) incubated for 6 hrs by Western blot based cell based method	3-(aryl or heteroaryl) methyleneindolin-2-one derivatives as inhibitors of cancer stem cell pathway kinases for the treatment of cancer
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

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7ZN	Ubigene A-549 RPS6KA6 KO	Cancer cell line	Male
CVCL_D9QZ	Ubigene HEK293 RPS6KA6 KO	Transformed cell line	Female
CVCL_TJ68	HAP1 RPS6KA6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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