RPS6KA2

Summary

RPS6KA2 (ribosomal protein S6 kinase A2, HGNC:10431) is a protein-coding gene on chromosome 6q27, encoding Ribosomal protein S6 kinase alpha-2 (Q15349). Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of transcription factors, regulates translation, and mediates cellular proliferation, survival, and differentiation.

This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains two 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. Alternative splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 6196 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 119 total
• Druggable target: yes — 29 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_021135

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10431
Approved symbol	RPS6KA2
Name	ribosomal protein S6 kinase A2
Location	6q27
Locus type	gene with protein product
Status	Approved
Aliases	RSK3, HU-2
Ensembl gene	ENSG00000071242
Ensembl biotype	protein_coding
OMIM	601685
Entrez	6196

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 19 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000265678, ENST00000366865, ENST00000405189, ENST00000481261, ENST00000491836, ENST00000503859, ENST00000506565, ENST00000507350, ENST00000507371, ENST00000509742, ENST00000510118, ENST00000511034, ENST00000512860, ENST00000714395, ENST00000907313, ENST00000907314, ENST00000907315, ENST00000907316, ENST00000907317, ENST00000907318, ENST00000935351, ENST00000967274

RefSeq mRNA: 5 — MANE Select: NM_021135 NM_001006932, NM_001318936, NM_001318937, NM_001318938, NM_021135

CCDS: CCDS34570, CCDS5294, CCDS83147, CCDS83148

Canonical transcript exons

ENST00000265678 — 21 exons

Exon	Start	End
ENSE00001180780	166626921	166627251
ENSE00002019815	166409364	166412887
ENSE00002043751	166469841	166469905
ENSE00002062015	166432401	166432490
ENSE00002087178	166430453	166430611
ENSE00003514608	166538668	166538784
ENSE00003514944	166418225	166418342
ENSE00003527168	166448724	166448849
ENSE00003552103	166413794	166413931
ENSE00003556287	166459449	166459551
ENSE00003583579	166451103	166451233
ENSE00003589144	166490671	166490741
ENSE00003600422	166498508	166498650
ENSE00003601265	166500887	166500924
ENSE00003631265	166510277	166510357
ENSE00003638980	166504506	166504612
ENSE00003660065	166419882	166419958
ENSE00003663686	166508203	166508282
ENSE00003673527	166531232	166531313
ENSE00003676059	166488833	166488921
ENSE00003691639	166423256	166423417

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.7819 / max 342.1206, expressed in 1484 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76685	4.8807	1151
76686	2.9472	1117
76684	1.8617	791
76689	1.0766	218
76682	0.4837	227
76688	0.3380	123
76690	0.1940	99

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior olivary complex	UBERON:0002127	97.66	gold quality
lower lobe of lung	UBERON:0008949	97.05	gold quality
medial globus pallidus	UBERON:0002477	96.96	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.71	gold quality
globus pallidus	UBERON:0001875	96.52	gold quality
inferior vagus X ganglion	UBERON:0005363	96.34	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.86	gold quality
cranial nerve II	UBERON:0000941	95.80	gold quality
right lung	UBERON:0002167	95.59	gold quality
spinal cord	UBERON:0002240	95.58	gold quality
corpus callosum	UBERON:0002336	95.40	gold quality
medulla oblongata	UBERON:0001896	95.32	gold quality
superior vestibular nucleus	UBERON:0007227	94.19	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.15	gold quality
lateral globus pallidus	UBERON:0002476	94.10	gold quality
sural nerve	UBERON:0015488	94.02	gold quality
middle frontal gyrus	UBERON:0002702	94.00	gold quality
upper lobe of lung	UBERON:0008948	93.78	gold quality
left ventricle myocardium	UBERON:0006566	93.71	gold quality
parietal lobe	UBERON:0001872	93.65	gold quality
postcentral gyrus	UBERON:0002581	93.61	gold quality
upper lobe of left lung	UBERON:0008952	93.55	gold quality
lung	UBERON:0002048	93.54	gold quality
subthalamic nucleus	UBERON:0001906	93.41	gold quality
midbrain	UBERON:0001891	93.33	gold quality
visceral pleura	UBERON:0002401	93.23	gold quality
substantia nigra	UBERON:0002038	93.22	gold quality
entorhinal cortex	UBERON:0002728	93.10	gold quality
ventral tegmental area	UBERON:0002691	93.03	gold quality
pons	UBERON:0000988	92.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	35.85
E-ANND-3	yes	22.39
E-GEOD-137537	yes	5.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

112 targeting RPS6KA2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-664B-3P	99.84	71.65	3590

Literature-anchored findings (GeneRIF, showing 22)

• Characterization of the terminal domain as a protein kinase (PMID:12016217)
• chronic activation CREB and p90RSK in the epileptic hippocampus may be closely associated with the histopathological changes of Ammon’s horn sclerosis (PMID:14646589)
• overexpressed in breast tumors (PMID:15112576)
• The accumulation of S6K2 in the nuclei of cancer cells and the correlation with the expression of PCNA and Ki-67 suggest the involvement of S6K2 in the regulation of malignant growth (PMID:15995633)
• p90Rsk-mediated modulation of Hdm2 nuclear is linked to cytoplasmic shuttling with the diminished ability of p53 to regulate cell cycle checkpoints that ultimately leads to transformation (PMID:16621805)
• The large C-terminal domain of ERK5 is not required for binding or activation of RSK by ERK5. (PMID:16626623)
• The above results suggest that RPS6KA2 is a putative tumour suppressor gene to explain allele loss at 6q27. (PMID:16878154)
• there is a functional link between S6K1 II and CK2 signaling, which involves the regulation of S6K1 II nuclear export by CK2-mediated phosphorylation of Ser-17 (PMID:16895915)
• Data show that genetic variation in RPS6KA1, RPS6KA2, and PRS6KB2 were associated with risk of developing colon cancer while only genetic variation in RPS6KA2 was associated with altering risk of rectal cancer. (PMID:21035469)
• p90RSK2 is dispensable for BCR-ABL-induced myeloid leukemia, but may be required for pathogenesis and lineage determination in FLT3-internal tandem duplication-induced hematopoietic transformation. (PMID:21527514)
• Data indicate that S6 kinase 2 (S6K2) can phosphorylate histone H3 at position Thr45, which may play a role during cell proliferation and/or differentiation. (PMID:23564320)
• 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)
• genetic association study in Han population in China: Data suggest that SNPs in RSK3 (rs2229712) and in MEK1 (rs28730804) demonstrate gene-gene interaction that affects antidepressant drug outcome in female patients with major depressive disorder. (PMID:23727904)
• Kinome screening revealed RPS6KA2 expression, in human pancreatic cancer cells, protects against erlotinib induced apoptosis. (PMID:24403857)
• RSK1 and 3 but not RSK2 are down-regulated in breast tumour and are associated with disease progression. RSK may be a key component in the progression and metastasis of breast cancer. (PMID:26977024)
• Data suggest that millisecond dynamic changes in PDZ1 domain conformation are responsible for higher affinity of scribble PDZ1 for phosphorylated ligands; oligopeptide fragments of RPS6KA2 and MCC were used as ligands in these nuclear magnetic resonance chemical shift experiments. (RPS6KA2 = ribosomal protein S6 kinase 2; MCC = mutated in colorectal cancer protein) (PMID:29144123)
• Elevated ribosomal protein S6 kinase A2 (RSK3) expression is responsible for BET bromodomain inhibitors (BETi) resistance. Proto-Oncogene Proteins c-jun (JunD)-dependent RSK3 transcription mediates BETi resistance. JunD/RSK3 signalling correlates to BET inhibition sensitivity. Loss of BRD4/FOXD3/miR-548d-3p axis enhances JunD/RSK3 signalling and determines BET inhibition resistance. (PMID:31937753)
• Genome-wide association study of cafe-au-lait macule number in neurofibromatosis type 1. (PMID:32869517)
• Multiomics analysis identifies key genes and pathways related to N6-methyladenosine RNA modification in ovarian cancer. (PMID:34550011)
• mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer. (PMID:36883564)
• TBX21 attenuates colorectal cancer progression via an ARHGAP29/RSK/GSK3beta dependent manner. (PMID:37067748)
• RSK3 switches cell fate: from stress-induced senescence to malignant progression. (PMID:38008756)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	rps6ka2	ENSDARG00000028469
mus_musculus	Rps6ka2	ENSMUSG00000023809
rattus_norvegicus	Rps6ka2	ENSRNOG00000013194
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): RPS6KA6 (ENSG00000072133), RPS6KA5 (ENSG00000100784), RPS6KB1 (ENSG00000108443), RPS6KA1 (ENSG00000117676), RPS6KA4 (ENSG00000162302), RPS6KB2 (ENSG00000175634), RPS6KA3 (ENSG00000177189)

Protein

Protein identifiers

Ribosomal protein S6 kinase alpha-2 — Q15349 (reviewed: Q15349)

Alternative names: 90 kDa ribosomal protein S6 kinase 2, MAP kinase-activated protein kinase 1c, Ribosomal S6 kinase 3, pp90RSK3

All UniProt accessions (9): Q15349, A0AAQ5BI00, B7Z3B5, D6R910, D6RA62, D6RD75, D6RE03, D6RHW7, F2Z2J1

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 transcription factors, regulates translation, and mediates cellular proliferation, survival, and differentiation. May function as tumor suppressor in epithelial ovarian cancer cells.

Subunit / interactions. Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation. Interacts with FBXO5; cooperate to induce the metaphase arrest of early blastomeres; increases and stabilizes interaction of FBXO5 with CDC20.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Widely expressed with higher expression in lung, skeletal muscle, brain, uterus, ovary, thyroid and prostate.

Post-translational modifications. Activated by phosphorylation at Ser-218 by PDPK1. Autophosphorylated on Ser-377, as part of the activation process. May be phosphorylated at Thr-356 and Ser-360 by MAPK1/ERK2 and MAPK3/ERK1. N-terminal myristoylation results in an activated kinase in the absence of added growth factors.

Activity regulation. Upon extracellular signal or mitogen stimulation, phosphorylated at Thr-570 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-377, allowing binding of PDPK1, which in turn phosphorylates Ser-218 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.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15349-1	1	yes
Q15349-2	2
Q15349-3	3

RefSeq proteins (5): NP_001006933, NP_001305865, NP_001305866, NP_001305867, NP_066958* (*=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
IPR042766	RSK3_STKc	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 (22 total): sequence conflict 6, binding site 4, domain 3, modified residue 2, splice variant 2, sequence variant 2, active site 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15349-F1	77.37	0.38

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): 184 (proton acceptor); 532 (proton acceptor)

Ligand- & substrate-binding residues (4): 65–73; 91; 421–429; 444

Post-translational modifications (2): 218, 377

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: 381 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_NUCLEAR_DIVISION, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_REGULATION_OF_MEIOTIC_NUCLEAR_DIVISION, GOZGIT_ESR1_TARGETS_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_DN, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_OOGENESIS, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE

GO Biological Process (17): oocyte maturation (GO:0001556), brain renin-angiotensin system (GO:0002035), signal transduction (GO:0007165), chemical synaptic transmission (GO:0007268), heart development (GO:0007507), negative regulation of cell population proliferation (GO:0008285), positive regulation of gene expression (GO:0010628), cardiac muscle cell apoptotic process (GO:0010659), intracellular signal transduction (GO:0035556), TORC1 signaling (GO:0038202), positive regulation of apoptotic process (GO:0043065), negative regulation of cell cycle (GO:0045786), negative regulation of meiotic nuclear division (GO:0045835), heart contraction (GO:0060047), regulation of protein processing (GO:0070613), cellular response to carbohydrate stimulus (GO:0071322), protein phosphorylation (GO:0006468)

GO Molecular Function (12): magnesium ion binding (GO:0000287), protein serine/threonine kinase activity (GO:0004674), ribosomal protein S6 kinase activity (GO:0004711), protein serine/threonine/tyrosine kinase activity (GO:0004712), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), synapse (GO:0045202), meiotic spindle (GO:0072687), spindle (GO:0005819), 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
protein kinase activity	3
cellular anatomical structure	3
negative regulation of cellular process	2
intracellular anatomical structure	2
intracellular membraneless organelle	2
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
nervous system process involved in regulation of systemic arterial blood pressure	1
regulation of blood volume by renin-angiotensin	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
anterograde trans-synaptic signaling	1
animal organ development	1
circulatory system development	1
cell population proliferation	1
regulation of cell population proliferation	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
striated muscle cell apoptotic process	1
signal transduction	1
TOR signaling	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
cell cycle	1
regulation of cell cycle	1
negative regulation of cell cycle process	1
regulation of meiotic nuclear division	1
negative regulation of meiotic cell cycle	1
negative regulation of nuclear division	1
meiotic nuclear division	1
heart process	1
blood circulation	1
protein processing	1
regulation of proteolysis	1

Protein interactions and networks

STRING

1686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPS6KA2	FOS	P01100	667
RPS6KA2	JUN	P05412	648
RPS6KA2	RPS6	P08227	610
RPS6KA2	TSC2	P49815	608
RPS6KA2	BCL2	P10415	606
RPS6KA2	RANBP3	Q9H6Z4	591
RPS6KA2	CREB1	P16220	583
RPS6KA2	AKAP6	Q13023	568
RPS6KA2	RPTOR	Q8N122	566
RPS6KA2	SFT2D1	Q8WV19	554
RPS6KA2	DUSP6	Q16828	553
RPS6KA2	MTOR	P42345	546
RPS6KA2	SLCO6A1	Q86UG4	537
RPS6KA2	ATP7A	Q04656	527
RPS6KA2	BCL2L1	Q07817	519

IntAct

80 interactions, top by confidence:

A	B	Type	Score
RPS6KA2	MAPK1	psi-mi:“MI:0914”(association)	0.910
MAPK1	RPS6KA2	psi-mi:“MI:0915”(physical association)	0.910
FYN	HSP90AA1	psi-mi:“MI:0914”(association)	0.800
RPS6KA1	RPS6KA3	psi-mi:“MI:0914”(association)	0.790
SCRIB	RPS6KA2	psi-mi:“MI:0407”(direct interaction)	0.770
RPS6KA2	SCRIB	psi-mi:“MI:0915”(physical association)	0.770
MAPK3	MAPK1	psi-mi:“MI:0914”(association)	0.770
RPS6KA2	MAPK3	psi-mi:“MI:2364”(proximity)	0.710
RPS6KA2	CSNK2B	psi-mi:“MI:0915”(physical association)	0.660
CSNK2B	RPS6KA5	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
SHANK1	RPS6KA2	psi-mi:“MI:0407”(direct interaction)	0.560
KLF11	RPS6KA2	psi-mi:“MI:0915”(physical association)	0.560
APP	RPS6KA2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (228): FAT1 (Affinity Capture-MS), GRSF1 (Affinity Capture-MS), MAPK1 (Affinity Capture-MS), SHROOM3 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), RPS6KA2 (Co-localization), RPS6KA2 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS)

ESM2 similar proteins: A2XFF4, B8BBT7, F1M7Y5, O14936, O22971, O61661, O70589, O74536, O75582, O80902, P18654, P23298, P24723, P28867, P41743, P51812, P54645, P54646, P92958, Q02111, Q02723, Q04759, Q05655, Q09137, Q13131, Q15349, Q16975, Q28948, Q38997, Q5EG47, Q5R4K3, Q5R4K9, Q5RD00, Q5RDH5, Q61RA2, Q62074, Q64617, Q6PFQ0, Q7TPS0, Q852Q0

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

12 interactions.

A	Effect	B	Mechanism
MAPK1	up-regulates	RPS6KA2	phosphorylation
RPS6KA2	down-regulates	NFKBIA	phosphorylation
RPS6KA2	down-regulates	BAD	phosphorylation
RPS6KA2	“down-regulates activity”	BAD	phosphorylation
Gbeta	up-regulates	RPS6KA2	phosphorylation
ERK1/2	up-regulates	RPS6KA2	phosphorylation
MTOR	“up-regulates activity”	RPS6KA2	phosphorylation
RPS6KA2	“down-regulates activity”	MRE11	phosphorylation
MAPK3	up-regulates	RPS6KA2	phosphorylation
RPS6KA2	“up-regulates activity”	L1CAM	phosphorylation
RPS6KA2	“down-regulates activity”	NR4A1	phosphorylation
1-[4-Amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-fluoroethanone	“down-regulates activity”	RPS6KA2	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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	70.0×	2e-07
MAPK targets/ Nuclear events mediated by MAP kinases	5	56.6×	5e-07
MAP kinase activation	6	38.6×	3e-07
Signaling by ERBB2	5	36.0×	4e-06
Nuclear Events (kinase and transcription factor activation)	5	36.0×	4e-06
Interleukin-17 signaling	6	31.7×	7e-07
Toll Like Receptor 10 (TLR10) Cascade	7	31.4×	2e-07
Toll Like Receptor 5 (TLR5) Cascade	7	31.4×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
MAPK cascade	5	12.3×	4e-03
protein phosphorylation	9	9.9×	3e-04
positive regulation of ERK1 and ERK2 cascade	7	9.6×	1e-03
intracellular signal transduction	10	6.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	73
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

5264 predictions. Top by Δscore:

Variant	Effect	Δscore
6:166413810:T:TA	donor_gain	1.0000
6:166418223:A:AC	donor_gain	1.0000
6:166418224:C:CC	donor_gain	1.0000
6:166423250:GCTCA:G	donor_loss	1.0000
6:166423251:CTCA:C	donor_loss	1.0000
6:166423252:TCA:T	donor_loss	1.0000
6:166423253:CACC:C	donor_loss	1.0000
6:166423254:A:T	donor_loss	1.0000
6:166423255:C:CA	donor_loss	1.0000
6:166430451:AC:A	donor_gain	1.0000
6:166430451:ACCC:A	donor_gain	1.0000
6:166430452:CC:C	donor_gain	1.0000
6:166430452:CCCC:C	donor_gain	1.0000
6:166430454:C:CA	donor_gain	1.0000
6:166430607:TAGAC:T	acceptor_gain	1.0000
6:166430608:AGAC:A	acceptor_gain	1.0000
6:166430609:GAC:G	acceptor_gain	1.0000
6:166430609:GACCT:G	acceptor_loss	1.0000
6:166430611:CCTG:C	acceptor_loss	1.0000
6:166430612:C:CC	acceptor_gain	1.0000
6:166430613:T:A	acceptor_loss	1.0000
6:166432396:CTCA:C	donor_loss	1.0000
6:166432397:TCA:T	donor_loss	1.0000
6:166432398:CACAT:C	donor_loss	1.0000
6:166432399:A:AC	donor_gain	1.0000
6:166432399:ACAT:A	donor_gain	1.0000
6:166432399:ACATC:A	donor_gain	1.0000
6:166432400:C:CA	donor_loss	1.0000
6:166432400:C:CC	donor_gain	1.0000
6:166432400:CA:C	donor_gain	1.0000

AlphaMissense

4819 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:166451181:G:C	F376L	1.000
6:166451181:G:T	F376L	1.000
6:166451183:A:G	F376L	1.000
6:166459468:G:C	F352L	1.000
6:166459468:G:T	F352L	1.000
6:166459470:A:G	F352L	1.000
6:166459480:A:C	F348L	1.000
6:166459480:A:T	F348L	1.000
6:166459482:A:G	F348L	1.000
6:166490712:G:C	F259L	1.000
6:166490712:G:T	F259L	1.000
6:166490714:A:G	F259L	1.000
6:166490716:G:T	P258Q	1.000
6:166498518:C:T	G246D	1.000
6:166498526:C:A	W243C	1.000
6:166498526:C:G	W243C	1.000
6:166498528:A:G	W243R	1.000
6:166498528:A:T	W243R	1.000
6:166498531:A:G	W242R	1.000
6:166498531:A:T	W242R	1.000
6:166498534:C:G	D241H	1.000
6:166498572:G:T	P228H	1.000
6:166498581:T:C	Y225C	1.000
6:166498582:A:G	Y225H	1.000
6:166498593:C:A	G221V	1.000
6:166498593:C:T	G221E	1.000
6:166498594:C:A	G221W	1.000
6:166498594:C:G	G221R	1.000
6:166498594:C:T	G221R	1.000
6:166498595:G:C	C220W	1.000

dbSNP variants (sampled 300 via entrez): RS1000009543 (6:166469971 G>A,T), RS1000011298 (6:166520497 A>G), RS1000015702 (6:166671370 A>C), RS1000016560 (6:166557004 G>A), RS1000016907 (6:166408935 T>C), RS1000030145 (6:166650510 G>A), RS1000041194 (6:166579315 C>T), RS1000053192 (6:166764148 A>G), RS1000053601 (6:166539139 C>T), RS1000055052 (6:166481836 G>A,T), RS1000058623 (6:166593862 G>A,T), RS1000065045 (6:166687883 G>A), RS1000065489 (6:166516863 G>A,T), RS1000073026 (6:166521913 C>T), RS1000075665 (6:166778212 G>C)

Disease associations

OMIM: gene MIM:601685 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): autism spectrum disorder (MONDO:0005258)

Orphanet (1): NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001725_92	Inflammatory bowel disease	7.000000e-21
GCST001786_17	Dental caries	1.000000e-07
GCST002361_2	Smooth-surface caries	7.000000e-06
GCST002587_9	Blood pressure (smoking interaction)	8.000000e-07
GCST003602_2	Inflammatory bowel disease	1.000000e-06
GCST006136_7	Alzheimer’s disease progression score	2.000000e-06
GCST007672_13	3-month functional outcome in ischaemic stroke (modified Rankin score)	6.000000e-06
GCST008103_130	Bipolar disorder	2.000000e-06
GCST008103_31	Bipolar disorder	4.000000e-08
GCST008115_16	Bipolar I disorder	7.000000e-08
GCST008151_51	Waist circumference	8.000000e-06
GCST008160_10	Waist circumference	8.000000e-06
GCST008758_61	Pre-treatment viral load in HIV-1 infection	8.000000e-17
GCST009733_58	Urinary metabolite levels in chronic kidney disease	3.000000e-11
GCST011161_5	Macrovascular complications in type 2 diabetes	4.000000e-08
GCST011464_1	Café-au-lait macule number in neurofibromatosis type1	4.000000e-06
GCST011743_45	HDL cholesterol levels in HIV infection	9.000000e-06
GCST012465_57	Bipolar disorder	4.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006526	pack-years measurement
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0009603	stroke outcome severity measurement
EFO:0009963	bipolar I disorder
EFO:0010125	viral load
EFO:0005116	urinary metabolite measurement
EFO:0010977	macrovascular complications of diabetes
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL3832633 (PROTEIN FAMILY), CHEMBL3906 (SINGLE PROTEIN), CHEMBL4523616 (PROTEIN FAMILY), CHEMBL4630724 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

29 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 200,393 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2103743	TOFACITINIB CITRATE	4	1,672
CHEMBL221959	TOFACITINIB	4	10,408
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
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL14762	SELICICLIB	2	3,787
CHEMBL1721885	SU-014813	2	363
CHEMBL31574	FISETIN	2	7,745
CHEMBL384304	RG-547	2	93
CHEMBL495727	AT-9283	2
CHEMBL513909	BI-2536	2
CHEMBL572878	TOZASERTIB	2
CHEMBL607707	PELITINIB	2
CHEMBL3544960	AT-13148	1
CHEMBL1908394	GSK-461364	1
CHEMBL1908397	KW-2449	1
CHEMBL3128043	PF-03758309	1
CHEMBL574738	AST-487	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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 25b [PMID: 22564207]	Inhibition	8.15	pIC50
BI-D1870	Inhibition	7.74	pIC50

Binding affinities (BindingDB)

257 measured of 270 human assays (270 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(3S,4R)-N-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-3,4-dimethyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	0.18 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1-ethylbenzimidazol-2-yl)-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide	IC50	0.25 nM	US-9150577: Heterocyclic compounds containing an indole core
N-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide	IC50	0.38 nM	US-9150577: Heterocyclic compounds containing an indole core
(3S,4R)-N-(1-benzylpyrazol-4-yl)-3,4-dimethyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	0.42 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1H-benzimidazol-2-yl)-4-methyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	0.59 nM	US-9150577: Heterocyclic compounds containing an indole core
(4R)-N-(1-benzylpyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	0.6 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1-ethylbenzimidazol-2-yl)-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	0.6 nM	US-9150577: Heterocyclic compounds containing an indole core
4,4-dimethyl-N-(1-methylbenzimidazol-2-yl)-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide	IC50	0.62 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1-ethylbenzimidazol-2-yl)-4-methyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	0.63 nM	US-9150577: Heterocyclic compounds containing an indole core
(3R,4S)-N-(1-ethylbenzimidazol-2-yl)-3,4-dimethyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	0.64 nM	US-9150577: Heterocyclic compounds containing an indole core
(4R)-N-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-4-methyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	0.7 nM	US-9150577: Heterocyclic compounds containing an indole core
(5R)-N-(1-benzylpyrazol-4-yl)-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	0.71 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1H-benzimidazol-2-yl)-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	0.77 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1H-benzimidazol-2-yl)-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide	IC50	0.89 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1-ethylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	1.1 nM	US-9150577: Heterocyclic compounds containing an indole core
(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	IC50	1.1 nM	US-9150577: Heterocyclic compounds containing an indole core
N-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-4-methyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	1.3 nM	US-9150577: Heterocyclic compounds containing an indole core
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	IC50	1.3 nM	US-9150577: Heterocyclic compounds containing an indole core
(5R)-5-methyl-1-oxo-N-(1-propan-2-ylbenzimidazol-2-yl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	1.4 nM	US-9150577: Heterocyclic compounds containing an indole core
5-methyl-N-(1-methylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	1.6 nM	US-9150577: Heterocyclic compounds containing an indole core
Staurosporine	KD	1.7 nM
(4S,5S)-4,5-dimethyl-1-oxo-N-(1-propan-2-ylbenzimidazol-2-yl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	1.8 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1-benzylpyrazol-4-yl)-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide	IC50	1.8 nM	US-9150577: Heterocyclic compounds containing an indole core
5-methyl-1-oxo-N-(1-propan-2-ylbenzimidazol-2-yl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	1.8 nM	US-9150577: Heterocyclic compounds containing an indole core
N-[1-[(3,5-dimethylphenyl)methyl]pyrazol-4-yl]-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	1.9 nM	US-9150577: Heterocyclic compounds containing an indole core
(3R,4S)-N-(1-benzylpyrazol-4-yl)-3,4-dimethyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	1.9 nM	US-9150577: Heterocyclic compounds containing an indole core
(4R)-4-methyl-1-oxo-N-(1-propan-2-ylbenzimidazol-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	1.9 nM	US-9150577: Heterocyclic compounds containing an indole core
1-oxo-N-[1-(pyridin-4-ylmethyl)pyrazol-4-yl]-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	1.9 nM	US-9150577: Heterocyclic compounds containing an indole core
5,5-dimethyl-1-oxo-N-(1-propan-2-ylbenzimidazol-2-yl)-3,4-dihydro-2H-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	2 nM	US-9150577: Heterocyclic compounds containing an indole core
(4S,5S)-N-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-4,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	2 nM	US-9150577: Heterocyclic compounds containing an indole core
(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
N-[2-(cyclopentylcarbamoyl)-1-methylimidazol-4-yl]-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	2.1 nM	US-9150577: Heterocyclic compounds containing an indole core
4-methyl-N-(1-methylbenzimidazol-2-yl)-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	2.2 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(6-chloro-1H-benzimidazol-2-yl)-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	2.5 nM	US-9150577: Heterocyclic compounds containing an indole core
N-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	2.6 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(6-methyl-1H-benzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	3 nM	US-9150577: Heterocyclic compounds containing an indole core
(3R,4S)-3,4-dimethyl-1-oxo-N-(1-propan-2-ylbenzimidazol-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	3.4 nM	US-9150577: Heterocyclic compounds containing an indole core
1-oxo-N-(6-propylsulfonyl-1H-benzimidazol-2-yl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	3.6 nM	US-9150577: Heterocyclic compounds containing an indole core
N-[2-(cyclopentylcarbamoyl)-1-methylimidazol-4-yl]-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide	IC50	3.7 nM	US-9150577: Heterocyclic compounds containing an indole core
N-[1-[[3-(dimethylamino)phenyl]methyl]pyrazol-4-yl]-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	3.8 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1-benzylpyrazol-4-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	4 nM	US-9150577: Heterocyclic compounds containing an indole core
(3S,4R)-3,4-dimethyl-N-(5-methyl-1,2-oxazol-3-yl)-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	4 nM	US-9150577: Heterocyclic compounds containing an indole core
(3R,4S)-3,4-dimethyl-N-(1-methylpyrazol-4-yl)-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	4.3 nM	US-9150577: Heterocyclic compounds containing an indole core
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	IC50	4.4 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1H-benzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	4.4 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(1-ethyl-5-methylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	4.8 nM	US-9150577: Heterocyclic compounds containing an indole core
1-oxo-N-[1-(2,2,2-trifluoroethyl)benzimidazol-2-yl]-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	4.8 nM	US-9150577: Heterocyclic compounds containing an indole core
N-(6-cyano-1H-benzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide	IC50	4.9 nM	US-9150577: Heterocyclic compounds containing an indole core
(3S,4S)-N-(1-ethylbenzimidazol-2-yl)-3,4-dimethyl-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	5 nM	US-9150577: Heterocyclic compounds containing an indole core
4-methyl-N-(1-methylpyrazol-4-yl)-1-oxo-3,4-dihydro-2H-pyrazino[1,2-a]indole-7-carboxamide	IC50	5.1 nM	US-9150577: Heterocyclic compounds containing an indole core

ChEMBL bioactivities

407 potent at pChembl≥5 of 413 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.97	IC50	0.108	nM	STAUROSPORINE
9.85	IC50	0.14	nM	STAUROSPORINE
9.74	IC50	0.18	nM	CHEMBL3956539
9.64	IC50	0.227	nM	STAUROSPORINE
9.60	IC50	0.25	nM	CHEMBL3945993
9.42	IC50	0.38	nM	CHEMBL3903528
9.38	IC50	0.42	nM	CHEMBL3900064
9.23	IC50	0.59	nM	CHEMBL3959915
9.22	IC50	0.6	nM	CHEMBL4109143
9.22	IC50	0.6	nM	CHEMBL3955947
9.21	IC50	0.62	nM	CHEMBL3908561
9.20	IC50	0.63	nM	CHEMBL3972132
9.19	IC50	0.64	nM	CHEMBL4108521
9.15	IC50	0.7	nM	CHEMBL4113357
9.15	IC50	0.71	nM	CHEMBL4111661
9.11	IC50	0.77	nM	CHEMBL3951802
9.05	IC50	0.89	nM	CHEMBL3985027
9.00	IC50	1	nM	AT-9283
8.96	IC50	1.1	nM	CHEMBL1933280
8.96	IC50	1.1	nM	CHEMBL1933288
8.89	IC50	1.3	nM	CHEMBL3939884
8.89	IC50	1.3	nM	CHEMBL3942136
8.85	IC50	1.4	nM	CHEMBL4112559
8.80	IC50	1.6	nM	CHEMBL3918100
8.74	IC50	1.8	nM	CHEMBL3904474
8.74	IC50	1.8	nM	CHEMBL3963988
8.74	IC50	1.8	nM	CHEMBL3900130
8.72	IC50	1.9	nM	CHEMBL3980724
8.72	IC50	1.9	nM	CHEMBL4113926
8.72	IC50	1.9	nM	CHEMBL4109800
8.72	IC50	1.9	nM	CHEMBL1933278
8.70	IC50	2	nM	CHEMBL3965519
8.70	IC50	2	nM	CHEMBL3910099
8.68	IC50	2.1	nM	CHEMBL4111985
8.68	IC50	2.1	nM	CHEMBL3966733
8.66	IC50	2.2	nM	CHEMBL3969149
8.60	IC50	2.5	nM	CHEMBL3946668
8.59	IC50	2.6	nM	CHEMBL3917125
8.52	IC50	3	nM	CHEMBL3916626
8.49	IC50	3.23	nM	CHEMBL573107
8.48	IC50	3.33	nM	CHEMBL5980821
8.47	IC50	3.4	nM	CHEMBL4107750
8.44	IC50	3.6	nM	CHEMBL4110776
8.43	IC50	3.7	nM	CHEMBL1933142
8.42	IC50	3.79	nM	CHEMBL3909070
8.42	IC50	3.8	nM	CHEMBL3936149
8.40	IC50	4	nM	CHEMBL3298194
8.40	IC50	4	nM	CHEMBL3921354
8.40	IC50	4	nM	CHEMBL3916789
8.40	Kd	4	nM	CHEMBL4576489

PubChem BioAssay actives

118 with measured affinity, of 1045 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	1715179: Inhibition of human RSK3 using KKLNRTLSVA as substrate by [gamma-33P]-ATP assay	ic50	0.0001	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	412605: Inhibition of Rsk3	ic50	0.0010	uM
2,6-difluoro-4-[4-(4-morpholin-4-ylphenyl)-3-pyridinyl]phenol	1662139: Inhibition of RSK3 (unknown origin)	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]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526311: Binding affinity to recombinant human full length N-terminal GST-tagged RPS6KA2 expressed in baculovirus expression system using S6K peptide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0040	uM
7-(1H-benzimidazol-4-yl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.0040	uM
2,6-difluoro-4-[4-[4-(4-methylpiperazin-1-yl)phenyl]-3-pyridinyl]phenol	1781667: Inhibition of full length recombinant GST-tagged human RSK3 expressed in insect cell using biotin-labelled AGAGRSRHSSYPAGT-OH as substrate in presence of ATP	ic50	0.0040	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	676097: Inhibition of human Rsk3	ic50	0.0070	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	1526311: Binding affinity to recombinant human full length N-terminal GST-tagged RPS6KA2 expressed in baculovirus expression system using S6K peptide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0080	uM
2-(3,5-difluoro-4-hydroxyanilino)-5,7-dimethyl-8-(3-methylbutyl)-7H-pteridin-6-one	2077314: Inhibition of RSK3 (14 to 462 residues) (unknown origin) using KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK peptide as substrate incubated for 10 mins in presence of [gamma-32p]ATP	ic50	0.0100	uM
7-(2-fluoro-6-methoxyphenyl)-N-[4-methoxy-3-[(3S)-pyrrolidin-3-yl]oxyphenyl]-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.0100	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	2167988: Inhibition of human RSK3 assessed as inhibition constant in presence of ATP	ki	0.0110	uM
Brigatinib	2182802: Inhibition of human RPS6kA2 using KKLNRTLSVA as substrate in presence of [gamma33P]-ATP by HotSpot assay	ic50	0.0130	uM
Sunitinib	436050: Binding constant for RPS6KA2(Kin.Dom.1 - N-terminal) kinase domain	kd	0.0170	uM
7-(2-methoxyphenyl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.0200	uM
7-(2-fluoro-6-methoxyphenyl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.0200	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	625127: Binding constant for RSK3(Kin.Dom.1-N-terminal) kinase domain	kd	0.0330	uM
7-(5-fluoro-2-methoxyphenyl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.0400	uM
7-(2-methoxy-4-methylphenyl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.0400	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	508078: Binding affinity to RPS6KA5(Kin.Dom.1-N-terminal)	kd	0.0420	uM
7-(1H-indazol-7-yl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.0500	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625127: Binding constant for RSK3(Kin.Dom.1-N-terminal) kinase domain	kd	0.0580	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	1823477: Inhibition of RSK3 (unknown origin) in human CAL-27 cells measured after 6 hrs by select screen kinase assay	ic50	0.0610	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
N-(3,4-dimethoxyphenyl)-7-(2-fluoro-6-methoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.0700	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
Ruxolitinib	624805: Binding constant for RSK3(Kin.Dom.2-C-terminal) kinase domain	kd	0.1500	uM
N-(3,5-dimethoxyphenyl)-7-(2-fluoro-6-methoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.2100	uM
3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione	625127: Binding constant for RSK3(Kin.Dom.1-N-terminal) kinase domain	kd	0.2200	uM
1-N-[7-(2-fluoro-6-methoxyphenyl)-1,3-benzoxazol-2-yl]-4-methoxybenzene-1,3-diamine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.2200	uM
7-(2-fluorophenyl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.2200	uM
Midostaurin	508078: Binding affinity to RPS6KA5(Kin.Dom.1-N-terminal)	kd	0.2400	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	436050: Binding constant for RPS6KA2(Kin.Dom.1 - N-terminal) kinase domain	kd	0.2600	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	436050: Binding constant for RPS6KA2(Kin.Dom.1 - N-terminal) kinase domain	kd	0.2800	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	436050: Binding constant for RPS6KA2(Kin.Dom.1 - N-terminal) kinase domain	kd	0.3100	uM
3-[[7-(2-fluoro-6-methoxyphenyl)-1,3-benzoxazol-2-yl]amino]benzenesulfonamide	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.3400	uM
[4-amino-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrimidin-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone	624805: Binding constant for RSK3(Kin.Dom.2-C-terminal) kinase domain	kd	0.3900	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	436050: Binding constant for RPS6KA2(Kin.Dom.1 - N-terminal) kinase domain	kd	0.4100	uM
7-(2-fluoro-6-methoxyphenyl)-N-(3-methoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.4100	uM
7-(2-ethoxy-6-fluorophenyl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.4900	uM
7-(2,5-dimethyl-1H-imidazol-4-yl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.5600	uM
Tofacitinib	624805: Binding constant for RSK3(Kin.Dom.2-C-terminal) kinase domain	kd	0.6000	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625127: Binding constant for RSK3(Kin.Dom.1-N-terminal) kinase domain	kd	0.6200	uM
N-cyclohexyl-7-(2-fluoro-6-methoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.6200	uM
7-(2-fluoro-6-methoxyphenyl)-N-(6-methoxy-2-pyridinyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.6200	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	624805: Binding constant for RSK3(Kin.Dom.2-C-terminal) kinase domain	kd	0.7000	uM
N-(3-ethoxyphenyl)-7-(2-fluoro-6-methoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.7300	uM
4-N-(3-aminopropyl)-2-N-(2-methylsulfonyl-3,4-dihydro-1H-isoquinolin-6-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine	2026722: Inhibition of p70S6K (unknown origin) using peptide substrate incubated for 1 hrs in presence of ATP by fluorescence microplate reader	ic50	0.8348	uM
29-(dimethylamino)-4,14,24,30-tetrazaheptacyclo[26.2.2.14,11.117,24.05,10.012,16.018,23]tetratriaconta-1(30),5,7,9,11(34),12(16),17(33),18,20,22,28,31-dodecaene-13,15-dione	306982: Inhibition of human Rsk2	ic50	0.8500	uM
2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one	2008191: Inhibition of RSK3 (unknown origin)	ic50	0.8910	uM
7-(2-fluoro-6-propan-2-yloxyphenyl)-N-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol-2-amine	1223755: Inhibition of recombinant full length RSK2 (unknown origin) using biotin-AGAGRSRHSSYPAGT-OH as substrate after 150 mins	ic50	0.9700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
sodium arsenite	affects methylation, affects splicing, decreases expression, increases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, increases mutagenesis	4
Estradiol	increases expression, affects cotreatment, decreases expression, affects expression, affects binding	4
Cadmium Chloride	decreases expression, increases abundance, increases expression	4
bisphenol A	affects methylation, affects cotreatment, increases expression	3
Acetaminophen	decreases expression, increases expression	2
Cisplatin	affects expression, affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	affects methylation, decreases expression	2
aristolochic acid I	decreases expression	1
afuresertib	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
beta-lapachone	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	increases abundance, affects methylation	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
aflatoxin B2	increases methylation	1
hydroquinone	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
pentanal	increases expression	1
caffeic acid phenethyl ester	decreases reaction, increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1

ChEMBL screening assays

448 unique, capped per target: 446 binding, 1 admet, 1 functional

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
CHEMBL5209997	Functional	Affinity Phenotypic Cellular interaction (Cellular mechanistic pACC assay using IMR-32 neuroblastoma cells) EUB0000707a RPS6KA1	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D8US	Ubigene HCT 116 RPS6KA2 KO	Cancer cell line	Male
CVCL_D9QW	Ubigene HEK293 RPS6KA2 KO	Transformed cell line	Female
CVCL_E0N0	Ubigene HeLa RPS6KA2 KO	Cancer cell line	Female
CVCL_TJ61	HAP1 RPS6KA2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
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NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
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NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
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NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
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NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
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NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder