RPS6

Summary

RPS6 (ribosomal protein S6, HGNC:10429) is a protein-coding gene on chromosome 9p22.1, encoding Small ribosomal subunit protein eS6 (P62753). Component of the 40S small ribosomal subunit. In precision oncology, RPS6 PHOSPHORYLATION confers sensitivity to Everolimus in Gastric Adenocarcinoma (CIViC Level D). It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a cytoplasmic ribosomal protein that is a component of the 40S subunit. The protein belongs to the S6E family of ribosomal proteins. It is the major substrate of protein kinases in the ribosome, with subsets of five C-terminal serine residues phosphorylated by different protein kinases. Phosphorylation is induced by a wide range of stimuli, including growth factors, tumor-promoting agents, and mitogens. Dephosphorylation occurs at growth arrest. The protein may contribute to the control of cell growth and proliferation through the selective translation of particular classes of mRNA. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.

Source: NCBI Gene 6194 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 36 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_001010

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10429
Approved symbol	RPS6
Name	ribosomal protein S6
Location	9p22.1
Locus type	gene with protein product
Status	Approved
Aliases	S6, eS6
Ensembl gene	ENSG00000137154
Ensembl biotype	protein_coding
OMIM	180460
Entrez	6194

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 26 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000315377, ENST00000380381, ENST00000380384, ENST00000380394, ENST00000498815, ENST00000889072, ENST00000889073, ENST00000889074, ENST00000889075, ENST00000889076, ENST00000889077, ENST00000919419, ENST00000919420, ENST00000919421, ENST00000919422, ENST00000919423, ENST00000919424, ENST00000919425, ENST00000919426, ENST00000919427, ENST00000919428, ENST00000948750, ENST00000948751, ENST00000948752, ENST00000948753, ENST00000948754, ENST00000948755

RefSeq mRNA: 1 — MANE Select: NM_001010 NM_001010

CCDS: CCDS6492

Canonical transcript exons

ENST00000380394 — 6 exons

Exon	Start	End
ENSE00000813418	19376494	19376651
ENSE00000927962	19378368	19378514
ENSE00000927963	19378708	19378918
ENSE00001484819	19380190	19380236
ENSE00001950299	19375715	19376388
ENSE00003638746	19379487	19379618

Expression profiles

Bgee: expression breadth ubiquitous, 311 present calls, max score 99.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 360.8571 / max 5120.6039, expressed in 1827 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100162	358.7901	1827
100160	1.3280	812
100161	0.7391	411

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of hip	UBERON:0001554	99.97	gold quality
upper leg skin	UBERON:0004262	99.96	gold quality
mammary duct	UBERON:0001765	99.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.94	gold quality
pylorus	UBERON:0001166	99.94	gold quality
epithelium of mammary gland	UBERON:0003244	99.94	gold quality
pancreatic ductal cell	CL:0002079	99.93	gold quality
left ovary	UBERON:0002119	99.93	gold quality
ileal mucosa	UBERON:0000331	99.92	gold quality
ovary	UBERON:0000992	99.92	gold quality
mammalian vulva	UBERON:0000997	99.92	gold quality
germinal epithelium of ovary	UBERON:0001304	99.92	gold quality
skin of abdomen	UBERON:0001416	99.92	gold quality
mammary gland	UBERON:0001911	99.92	gold quality
right ovary	UBERON:0002118	99.92	gold quality
ventricular zone	UBERON:0003053	99.92	gold quality
ganglionic eminence	UBERON:0004023	99.92	gold quality
caput epididymis	UBERON:0004358	99.92	gold quality
thoracic mammary gland	UBERON:0005200	99.92	gold quality
epithelial cell of pancreas	CL:0000083	99.91	gold quality
zone of skin	UBERON:0000014	99.91	gold quality
lymph node	UBERON:0000029	99.91	gold quality
urethra	UBERON:0000057	99.91	gold quality
endocervix	UBERON:0000458	99.91	gold quality
penis	UBERON:0000989	99.91	gold quality
cardia of stomach	UBERON:0001162	99.91	gold quality
parotid gland	UBERON:0001831	99.91	gold quality
cervix squamous epithelium	UBERON:0006922	99.91	gold quality
body of uterus	UBERON:0009853	99.91	gold quality
type B pancreatic cell	CL:0000169	99.90	gold quality

Single-cell (SCXA)

Detected in 65 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	10382.67
E-HCAD-31	yes	6613.86
E-MTAB-11268	yes	5839.97
E-MTAB-6678	yes	4792.19
E-MTAB-10042	yes	4273.22
E-CURD-122	yes	102.31
E-MTAB-9221	yes	57.46
E-CURD-112	yes	40.01
E-HCAD-9	yes	29.72
E-MTAB-9067	yes	28.27
E-HCAD-35	yes	9.30
E-MTAB-9801	yes	6.48
E-GEOD-137537	yes	6.34
E-GEOD-114530	no	14166.76
E-CURD-98	no	12780.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CNBP, E2F4, MYC, ZBED1, ZBTB4

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Rheb is a mediator of RPS6. (PMID:12820960)
• IFNgamma-activated p70 S6 kinase phosphorylates the 40S S6 ribosomal protein on serines 235/236, to regulate IFNgamma-dependent mRNA translation. (PMID:15051500)
• Cortical tuber giant cells in a case of epileptogenic tuberous sclerosis showed predominantly nuclear hamartin, cytosolic tuberin, and hyperphosphorylation of S6. (PMID:15477556)
• Genetic alterations of TP53 and RPS6 were different in different areas of the same oral squamous cell carcinoma tumor. (PMID:17565818)
• the phosphorylation of Tyr(1077) on LepRb during receptor activation, substantiate the hypothalamic regulation of STAT5 and S6 by leptin, and define the alternate LepRb signaling pathways (PMID:17726024)
• Structure, localization and molecular assembly in vitro and in vivo of a human rpS6, were examined using antibodies (Abs) prepared by immunizing rabbits with synthetic peptides. (PMID:18039684)
• The level of phosphorylated S6 ribosomal protein expression was predictive of early tumor response to the mammalian target of rapamycin (mTOR)inhibitor, suggesting that this is a promising new predictive sarcoma marker for targeted mTOR inhibitor therapy (PMID:18157089)
• The results demonstrate that multiple muscarinic receptor subtypes regulate mTOR, and that both MAPK-dependent and -independent mechanisms may mediate the response in a cell context-specific manner. (PMID:18348264)
• rpS6, especially in its unphosphorylated form, is a selective mediator of TRAIL-induced apoptosis (PMID:18362888)
• Resistance exercise decreases eIF2Bepsilon phosphorylation and potentiates the feeding-induced stimulation of p70S6K1 and rpS6 in young men. (PMID:18565837)
• Basophilic inclusions from patients with adult-onset atypical motor neuron disease were distinctly labeled with the antibodies against poly(A)-binding protein 1, T cell intracellular antigen 1, and ribosomal protein S6. (PMID:18642007)
• The mTOR/S6 signal pathway is activated in refractory/relapsed aplastic anemia, and can be suppressed by rapamycin or CTLA-4Ig. (PMID:19954658)
• when exercise is performed in a fasted state, the increase in phosphorylation of signalling molecules such as p70(S6k) and the S6 ribosomal protein in human muscle depends on the exercise volume (PMID:20617335)
• S240/244-phosphorylated S6 is predominantly nuclear but detectable in the cytoplasm, whereas S235/236-phosphorylated S6 is exclusively localized to the nucleus. (PMID:20625781)
• Data show that the mTOR effectors, 4EBP1, p70S6K and rpS6, are highly activated in cultured and primary FLT3-mutated acute myeloid leukemia (AML) cells. (PMID:21067588)
• RPS6 associates with multiple mRNAs containing a 5’ terminal oligopyrimidine tract. These findings expand our understanding of the mechanism(s) involved in ribosomal biogenesis and deregulated protein synthesis in diffuse large B-cell lymphoma (DLBCL). (PMID:21102526)
• Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. (PMID:21147110)
• Regulation of ribosomal protein S6 phosphorylation by casein kinase 1 and protein phosphatase 1. (PMID:21233202)
• Here, the authors show that ribosomal protein S6 (RPS6) interacts with LANA. (PMID:21734034)
• Downregulation of HELZ reduced translational initiation, resulting in the disassembly of polysomes, in a reduction of cell proliferation and hypophosphorylation of ribosomal protein S6. (PMID:21765940)
• High Ribosomal Protein S6 is associated with renal cell carcinoma metastases. (PMID:21792700)
• Nearly 20-fold more neurons contain pS6-positive granules in Alzheimer’s disease hippocampus compared to age-matched controls. (PMID:21968813)
• a novel mechanism for modulating the RPS6 function by PP1 and ATM which regulates cell growth and survival in response to DNA-damage stim (PMID:22451389)
• Suggest that p-S6 and the ratio of p-S6/S6 are closely relevant to tumor progression and have prognostic significance in esophageal squamous cell carcinoma. (PMID:22996377)
• S6 phosphorylation at S240/4 is strongly cell cycle-regulated. (PMID:23255058)
• Suggest phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia. (PMID:23765247)
• we report that phosphorylation of ribosomal protein S6 is greatly increased in BRCA1 deficient cells resistant to PARP inhibition (PMID:24831086)
• The expression levels of phospho-mTOR and phospho-S6RP may be potential predictive biomarkers for efficacy of everolimus in patients with metastatic renal cell carcinoma. (PMID:24886512)
• Resistance to Selumetinib (AZD6244) in colorectal cancer cell lines is mediated by p70S6K and RPS6 activation. (PMID:25379021)
• p-rpS6 is a robust post-treatment indicator of HER2 pathway-targeted therapy resistance (PMID:26329528)
• Hyperphosphorylation of ribosomal protein S6 predicts unfavorable clinical survival in non-small cell lung cancer (PMID:26490682)
• Data suggest ribosomal protein S6 (rpS6) as tumor marker for renal cell carcinoma. (PMID:26506236)
• reciprocal expression of p-AMPKa and p-S6 may be promising prognostic biomarkers in patients with gastric cancer (PMID:26520441)
• the aggregation of rpS6 at the nucleolus correlates to the phasing of cell cycle, beginning to concentrate in the nucleolus at later S phase and disaggregate at M phase. (PMID:26639987)
• single 60-min bout of peristaltic pulse external pneumatic compression transiently upregulates phosphorylated ribosomal protein s6 and the Akt-mTOR signalling cascade. (PMID:26769680)
• this study unveils an unprecedented correlation of mTOR activation with improved clinical outcome in patients with laryngeal carcinomas and uncovers the potential of p-S6 expression as a good prognostic biomarker and an inverse predictor of lymph node and distant metastases. (PMID:27119232)
• Study examined baseline levels of S6 phosphorylated at Ser235/236 (pS6Ser235/236) or Ser240/244 (pS6Ser240/244)and a possible effect of tau pathology. Findings argue against the idea that high levels of pS6Ser235/236 in neurons are a consequence of a higher expression of S6 protein and speak for an increased phosphorylation of S6 in intensely pS6Ser235/236-labeled neurons. (PMID:28119058)
• Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6(S240) expression is a potential predictive biomarker for response to treatment. (PMID:28232476)
• MiR-129-5p sensitized Her-2-positive breast cancer to trastuzumab by downregulating rpS6. (PMID:29258115)
• The overexpression of total and phosphorylated mTOR as well as phosphorylated rpS6 (residues 240-244) were associated with wild-type IDH1 only glioblastomas. The expression and phosphorylation of mTOR and phosphorylation of rpS6 at residues 240-244 were associated with a worse prognosis in glioblastomas. (PMID:29328863)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rps6	ENSDARG00000019778
mus_musculus	Rps6	ENSMUSG00000028495
rattus_norvegicus	Rps6	ENSRNOG00000049025
drosophila_melanogaster	RpS6	FBGN0261592
caenorhabditis_elegans	rps-6	WBGENE00004475

Protein

Protein identifiers

Small ribosomal subunit protein eS6 — P62753 (reviewed: P62753)

Alternative names: 40S ribosomal protein S6, Phosphoprotein NP33

All UniProt accessions (4): A2A3R5, A2A3R6, A2A3R7, P62753

UniProt curated annotations — full annotation on UniProt →

Function. Component of the 40S small ribosomal subunit. Plays an important role in controlling cell growth and proliferation through the selective translation of particular classes of mRNA. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.

Subunit / interactions. Component of the small ribosomal subunit. Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3.

Subcellular location. Cytoplasm. Nucleus. Nucleolus.

Post-translational modifications. Ribosomal protein S6 is the major substrate of protein kinases in eukaryote ribosomes. The phosphorylation is stimulated by growth factors, tumor promoting agents, and mitogens. It is dephosphorylated at growth arrest. Phosphorylated at Ser-235 and Ser-236 by RPS6KA1 and RPS6KA3; phosphorylation at these sites facilitates the assembly of the pre-initiation complex. Specifically hydroxylated (with R stereochemistry) at C-3 of Arg-137 by KDM8. Mono-ADP-ribosylation at Glu-35 by PARP16 inhibits polysome assembly and mRNA loading, thereby inhibiting protein translation.

Similarity. Belongs to the eukaryotic ribosomal protein eS6 family.

RefSeq proteins (1): NP_001001* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001377	Ribosomal_eS6	Family
IPR014401	Ribosomal_eS6-like	Family
IPR018282	Ribosomal_eS6_CS	Conserved_site

Pfam: PF01092

UniProt features (51 total): strand 16, modified residue 10, sequence conflict 6, helix 6, turn 5, mutagenesis site 2, compositionally biased region 2, chain 1, region of interest 1, cross-link 1, sequence variant 1

Structure

Experimental structures (PDB)

218 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6F4Q	X-RAY DIFFRACTION	1.12
6F4P	X-RAY DIFFRACTION	1.45
8GLP	ELECTRON MICROSCOPY	1.67
8QOI	ELECTRON MICROSCOPY	1.9
9O3W	ELECTRON MICROSCOPY	1.9
8YOO	ELECTRON MICROSCOPY	2
9C3H	ELECTRON MICROSCOPY	2
7R4X	ELECTRON MICROSCOPY	2.15
9I2D	ELECTRON MICROSCOPY	2.19
9PBE	ELECTRON MICROSCOPY	2.19
8YOP	ELECTRON MICROSCOPY	2.2
9O3V	ELECTRON MICROSCOPY	2.2
9O3Y	ELECTRON MICROSCOPY	2.2
8JDK	ELECTRON MICROSCOPY	2.26
8G5Y	ELECTRON MICROSCOPY	2.29
9S3D	ELECTRON MICROSCOPY	2.32
9RPV	ELECTRON MICROSCOPY	2.35
9S3B	ELECTRON MICROSCOPY	2.38
8K2C	ELECTRON MICROSCOPY	2.4
8XSX	ELECTRON MICROSCOPY	2.4
9SPF	ELECTRON MICROSCOPY	2.4
9SPI	ELECTRON MICROSCOPY	2.4
8JDL	ELECTRON MICROSCOPY	2.42
9S3C	ELECTRON MICROSCOPY	2.42
9QLO	ELECTRON MICROSCOPY	2.47
9P8B	ELECTRON MICROSCOPY	2.48
7XNY	ELECTRON MICROSCOPY	2.5
8JDJ	ELECTRON MICROSCOPY	2.5
9RUC	ELECTRON MICROSCOPY	2.5
8G60	ELECTRON MICROSCOPY	2.54

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62753-F1	94.33	0.94

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (11): 240, 242, 244, 247, 14, 35, 137, 148, 211, 235, 236

Mutagenesis-validated functional residues (2):

Position	Phenotype
137	abolishes hydroxylation by kdm8.
235–236	abolishes phosphorylation by pask.

Function

Pathways and Gene Ontology

Reactome pathways

61 pathways

ID	Pathway
R-HSA-156827	L13a-mediated translational silencing of Ceruloplasmin expression
R-HSA-156902	Peptide chain elongation
R-HSA-166208	mTORC1-mediated signalling
R-HSA-1799339	SRP-dependent cotranslational protein targeting to membrane
R-HSA-192823	Viral mRNA Translation
R-HSA-2408557	Selenocysteine synthesis
R-HSA-6790901	rRNA modification in the nucleus and cytosol
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-72649	Translation initiation complex formation
R-HSA-72689	Formation of a pool of free 40S subunits
R-HSA-72695	Formation of the ternary complex, and subsequently, the 43S complex
R-HSA-72702	Ribosomal scanning and start codon recognition
R-HSA-72706	GTP hydrolysis and joining of the 60S ribosomal subunit
R-HSA-72764	Eukaryotic Translation Termination
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9629569	Protein hydroxylation
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency
R-HSA-9725371	Nuclear events stimulated by ALK signaling in cancer
R-HSA-9735869	SARS-CoV-1 modulates host translation machinery
R-HSA-9754678	SARS-CoV-2 modulates host translation machinery
R-HSA-975956	Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)
R-HSA-9954714	PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA
R-HSA-9954716	ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-156842	Eukaryotic Translation Elongation
R-HSA-162582	Signal Transduction
R-HSA-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation
R-HSA-1643685	Disease

MSigDB gene sets: 403 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, YAGI_AML_WITH_INV_16_TRANSLOCATION, GNF2_TPT1, GCM_NPM1, MORF_UBE2I, MATTIOLI_MGUS_VS_PCL, GOBP_APICAL_JUNCTION_ASSEMBLY, HSIAO_HOUSEKEEPING_GENES, GOBP_RIBOSOME_ASSEMBLY, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (12): ribosomal small subunit assembly (GO:0000028), cytoplasmic translation (GO:0002181), rRNA processing (GO:0006364), translation (GO:0006412), positive regulation of cell population proliferation (GO:0008284), TOR signaling (GO:0031929), response to insulin (GO:0032868), ribosomal small subunit biogenesis (GO:0042274), glucose homeostasis (GO:0042593), positive regulation of apoptotic process (GO:0043065), cellular response to ethanol (GO:0071361), negative regulation of bicellular tight junction assembly (GO:1903347)

GO Molecular Function (5): RNA binding (GO:0003723), mRNA binding (GO:0003729), structural constituent of ribosome (GO:0003735), protein kinase binding (GO:0019901), protein binding (GO:0005515)

GO Cellular Component (18): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), small ribosomal subunit (GO:0015935), membrane (GO:0016020), cytosolic ribosome (GO:0022626), cytosolic small ribosomal subunit (GO:0022627), dendrite (GO:0030425), small-subunit processome (GO:0032040), cytoplasmic ribonucleoprotein granule (GO:0036464), cell body (GO:0044297), presynapse (GO:0098793), GABA-ergic synapse (GO:0098982), ribonucleoprotein complex (GO:1990904), ribosome (GO:0005840)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Cap-dependent Translation Initiation	4
Translation	2
rRNA processing in the nucleus and cytosol	2
Eukaryotic Translation Initiation	1
Eukaryotic Translation Elongation	1
MTOR signalling	1
Influenza Viral RNA Transcription and Replication	1
Selenoamino acid metabolism	1
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1
Signaling by ROBO receptors	1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1
Cellular response to starvation	1
Signaling by ALK fusions and activated point mutants	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
ribosome biogenesis	2
ribosome	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
intracellular membraneless organelle	2
synapse	2
protein-RNA complex assembly	1
ribosome assembly	1
ribosomal small subunit biogenesis	1
translation	1
RNA processing	1
rRNA metabolic process	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
intracellular signal transduction	1
response to peptide hormone	1
ribonucleoprotein complex biogenesis	1
carbohydrate homeostasis	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
response to ethanol	1
cellular response to alcohol	1
bicellular tight junction assembly	1
negative regulation of cell junction assembly	1
regulation of bicellular tight junction assembly	1
nucleic acid binding	1
RNA binding	1
structural molecule activity	1
kinase binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

367 interactions, top by confidence:

A	B	Type	Score
STAU1	RPS6	psi-mi:“MI:0403”(colocalization)	0.770
STAU1	RPLP0	psi-mi:“MI:0914”(association)	0.750
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
XPC	CETN3	psi-mi:“MI:0914”(association)	0.730
N	HNRNPR	psi-mi:“MI:0914”(association)	0.730
RPS6	RPL4	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RPS6	N	psi-mi:“MI:0915”(physical association)	0.700
RPS6	NPM1	psi-mi:“MI:0915”(physical association)	0.650
INAVA	CYTH3	psi-mi:“MI:0914”(association)	0.640
RACK1	RPS17	psi-mi:“MI:0915”(physical association)	0.610
NCBP1	RPS6	psi-mi:“MI:0915”(physical association)	0.580
NOM1	RPLP0	psi-mi:“MI:0914”(association)	0.530
EIF4E	RPS6	psi-mi:“MI:0914”(association)	0.530
RPS6	IPO7	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
PUM3	RRP8	psi-mi:“MI:0914”(association)	0.530
RPF1	ZNF324	psi-mi:“MI:0914”(association)	0.530
rep	RPS2	psi-mi:“MI:0914”(association)	0.530
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
DDX6	MCRIP1	psi-mi:“MI:0914”(association)	0.510
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (1558): RPS6 (Affinity Capture-Western), RPS6 (Affinity Capture-MS), RPS6 (Affinity Capture-MS), RPS6 (Co-fractionation), RPS6 (Co-fractionation), RPS6 (Affinity Capture-MS), RPS6 (Affinity Capture-MS), EIF5B (Co-fractionation), RPL10 (Co-fractionation), RPL10A (Co-fractionation), RPL12 (Co-fractionation), RPL15 (Co-fractionation), RPL27A (Co-fractionation), RPL35 (Co-fractionation), RPL37A (Co-fractionation)

ESM2 similar proteins: A0A1D8PL99, A2Q0R8, G1TM55, O01727, O44012, O48549, P05752, P0CX37, P0CX38, P0CX39, P0CX40, P25204, P29327, P39017, P41798, P47838, P48156, P49199, P51430, P62753, P62754, P62755, Q08069, Q2PQM1, Q4D2R9, Q4R4K6, Q4T8S6, Q54E24, Q54UU3, Q5E995, Q6BXH8, Q6C169, Q6CM04, Q6FJH3, Q6PBY1, Q74ZK3, Q7SYU0, Q8SRY0, Q90YR6, Q90YR8

Diamond homologs: A0A1D8PL99, A2BJZ7, A2STM7, A3CSP5, A3DMS1, A3MUD0, A4FWX0, A4WIK0, A4YIY0, A5UJM8, A6VGE7, A9A110, A9AAA5, B0R815, B6YW70, B8GJR6, B9LR51, C3MR04, C3MWZ2, C3MZ52, C3N772, C4KID0, C5A7C4, C6A2D7, G1TM55, O01727, O26360, O29739, O44012, O48549, O58349, P05752, P0CX37, P0CX38, P21509, P29327, P29345, P39017, P41798, P47838

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
RPS6KA1	up-regulates	RPS6	phosphorylation
RPS6K	up-regulates	RPS6	phosphorylation
ZBED1	“up-regulates quantity by expression”	RPS6	“transcriptional regulation”
RPS6KB1	“up-regulates activity”	RPS6	phosphorylation
miR-199a	“up-regulates activity”	RPS6
RPS6	up-regulates	“Ribosome biogenesis”
PAK2	unknown	RPS6	phosphorylation
RPS6	“form complex”	“40S cytosolic small ribosomal subunit”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 205 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
Ribosomal scanning and start codon recognition	12	15.8×	7e-10
Formation of the ternary complex, and subsequently, the 43S complex	10	14.9×	4e-08
Translation initiation complex formation	11	14.4×	9e-09
GTP hydrolysis and joining of the 60S ribosomal subunit	19	13.1×	1e-13
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	7	13.1×	3e-05
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	16	13.0×	1e-11
Eukaryotic Translation Initiation	6	12.8×	2e-04
Cap-dependent Translation Initiation	6	12.8×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
translational initiation	9	18.0×	5e-07
stress granule assembly	5	16.8×	1e-03
cytoplasmic translation	16	16.6×	2e-12
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	5	13.1×	3e-03
mRNA stabilization	6	12.3×	1e-03
ribosomal small subunit biogenesis	9	11.4×	2e-05
positive regulation of translation	9	11.4×	2e-05
positive regulation of interferon-beta production	5	10.9×	6e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

919 predictions. Top by Δscore:

Variant	Effect	Δscore
9:19376489:CTAA:C	donor_loss	1.0000
9:19376490:TAAC:T	donor_loss	1.0000
9:19376491:AAC:A	donor_loss	1.0000
9:19376492:A:AC	donor_gain	1.0000
9:19376492:ACCT:A	donor_loss	1.0000
9:19376493:C:A	donor_loss	1.0000
9:19376493:C:CC	donor_gain	1.0000
9:19376493:CCTT:C	donor_gain	1.0000
9:19376647:CTTAC:C	acceptor_gain	1.0000
9:19376648:TTAC:T	acceptor_gain	1.0000
9:19376649:TAC:T	acceptor_gain	1.0000
9:19376650:AC:A	acceptor_gain	1.0000
9:19376651:CC:C	acceptor_gain	1.0000
9:19376651:CCTA:C	acceptor_loss	1.0000
9:19378363:CCTAC:C	donor_loss	1.0000
9:19378364:CTA:C	donor_loss	1.0000
9:19378365:TA:T	donor_loss	1.0000
9:19378366:ACCTT:A	donor_loss	1.0000
9:19378367:CCTT:C	donor_gain	1.0000
9:19378391:A:AC	donor_gain	1.0000
9:19378392:C:CC	donor_gain	1.0000
9:19378392:CAA:C	donor_gain	1.0000
9:19378398:A:AC	donor_gain	1.0000
9:19378399:C:CC	donor_gain	1.0000
9:19378514:CCT:C	acceptor_gain	1.0000
9:19378515:C:CC	acceptor_gain	1.0000
9:19378516:T:C	acceptor_gain	1.0000
9:19378914:TAACC:T	acceptor_gain	1.0000
9:19378917:CC:C	acceptor_gain	1.0000
9:19378918:CC:C	acceptor_gain	1.0000

AlphaMissense

1609 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:19376616:G:T	R178S	1.000
9:19376621:A:C	I176S	1.000
9:19376621:A:T	I176N	1.000
9:19378394:A:T	V157D	1.000
9:19378406:A:T	V153D	1.000
9:19378424:A:G	L147P	1.000
9:19378429:G:C	F145L	1.000
9:19378429:G:T	F145L	1.000
9:19378431:A:G	F145L	1.000
9:19378431:A:T	F145I	1.000
9:19378442:A:C	I141S	1.000
9:19378442:A:G	I141T	1.000
9:19378442:A:T	I141N	1.000
9:19378453:T:A	R137S	1.000
9:19378453:T:G	R137S	1.000
9:19378454:C:G	R137T	1.000
9:19378463:C:T	G134D	1.000
9:19378464:C:G	G134R	1.000
9:19378493:A:G	L124P	1.000
9:19378731:A:G	L109P	1.000
9:19378731:A:T	L109H	1.000
9:19378740:A:G	L106P	1.000
9:19378752:A:T	V102E	1.000
9:19378757:G:C	C100W	1.000
9:19378758:C:T	C100Y	1.000
9:19378759:A:G	C100R	1.000
9:19378761:C:A	G99V	1.000
9:19378761:C:T	G99D	1.000
9:19378762:C:A	G99C	1.000
9:19378762:C:G	G99R	1.000

dbSNP variants (sampled 300 via entrez): RS1000379757 (9:19378547 A>C), RS1000883711 (9:19381193 A>G), RS1001249707 (9:19379251 C>T), RS1001303668 (9:19379343 C>G,T), RS1002505438 (9:19382235 T>C), RS1002866157 (9:19379880 C>A,G), RS1002877675 (9:19379957 T>A,C,G), RS1002969188 (9:19380219 A>G), RS1003628331 (9:19380455 C>A), RS1003629625 (9:19376955 T>TA), RS1005508191 (9:19375714 A>G), RS1005793401 (9:19380642 C>A,G), RS1006386680 (9:19380075 G>A), RS1007058384 (9:19381878 T>C,G), RS1007061138 (9:19377020 G>A)

Disease associations

OMIM: gene MIM:180460 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hemimegalencephaly (MONDO:0020492)

Orphanet (1): Hemimegalencephaly (Orphanet:99802)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009145_5	Total cholesterol levels	5.000000e-21

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065705	Hemimegalencephaly	C05.660.207.536.500; C10.500.507.400.249.500; C16.131.621.207.532.500; C16.131.666.507.400.249.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3351215 (SINGLE PROTEIN), CHEMBL3987582 (PROTEIN NUCLEIC-ACID COMPLEX)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds).

Molecule	Name	Phase	Patents
CHEMBL6067484	GENTAMICIN SULFATE	4

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
RPS6 PHOSPHORYLATION	Everolimus	Gastric Adenocarcinoma	Sensitivity/Response	CIViC D	EID930

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

ChEMBL bioactivities

50 potent at pChembl≥5 of 54 total, top 49 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.84	Kd	14.44	nM	CHEMBL3752910
7.84	ED50	14.44	nM	CHEMBL3752910
7.21	Kd	61.01	nM	CHEMBL5653589
7.21	ED50	61.01	nM	CHEMBL5653589
6.52	IC50	300	nM	CHEMBL4109308
6.42	IC50	380	nM	CHEMBL4109308
6.42	IC50	380	nM	CHEMBL4574496
6.41	IC50	390	nM	CHEMBL4126894
6.39	IC50	410	nM	CHEMBL4114159
6.35	IC50	450	nM	CHEMBL4126496
6.30	IC50	500	nM	CHEMBL4574496
6.30	IC50	500	nM	CHEMBL4560206
6.16	IC50	690	nM	CHEMBL4130157
6.15	IC50	710	nM	CHEMBL4108338
6.11	IC50	780	nM	CHEMBL4114159
6.09	IC50	820	nM	CHEMBL4109308
6.07	IC50	850	nM	CHEMBL4107559
6.07	IC50	850	nM	CHEMBL4533299
6.05	IC50	900	nM	CHEMBL4126894
6.05	IC50	900	nM	CHEMBL4126496
6.04	IC50	920	nM	CHEMBL4554909
5.97	IC50	1060	nM	CHEMBL4128388
5.89	IC50	1290	nM	CHEMBL4130157
5.86	IC50	1370	nM	CHEMBL4107559
5.84	IC50	1440	nM	CHEMBL4108338
5.81	IC50	1540	nM	CHEMBL4534859
5.76	IC50	1730	nM	CHEMBL4534859
5.69	IC50	2050	nM	CHEMBL4566239
5.68	IC50	2080	nM	CHEMBL4446635
5.66	IC50	2210	nM	CHEMBL4446635
5.66	EC50	2200	nM	CHEMBL4464929
5.64	IC50	2270	nM	CHEMBL4533299
5.63	IC50	2330	nM	CHEMBL4566239
5.62	IC50	2380	nM	CHEMBL4128388
5.58	IC50	2630	nM	CHEMBL4128250
5.55	IC50	2820	nM	CHEMBL4127458
5.53	IC50	2970	nM	CHEMBL4127311
5.51	IC50	3080	nM	CHEMBL4126072
5.46	IC50	3500	nM	CHEMBL4525277
5.44	IC50	3630	nM	CHEMBL4469712
5.39	IC50	4100	nM	CHEMBL4128560
5.37	IC50	4300	nM	CHEMBL4127016
5.36	IC50	4380	nM	CHEMBL4527910
5.16	IC50	7000	nM	CHEMBL4109308
5.13	IC50	7400	nM	CHLORAMPHENICOL SULFATE SALT
5.09	IC50	8040	nM	CHEMBL4128250
5.08	IC50	8370	nM	CHEMBL4128250
5.03	IC50	9320	nM	CHEMBL4127016
5.03	IC50	9240	nM	CHEMBL4128560

PubChem BioAssay actives

49 with measured affinity, of 227 total; 29 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149309: Binding affinity to human RPS6 incubated for 45 mins by Kinobead based pull down assay	kd	0.0144	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149309: Binding affinity to human RPS6 incubated for 45 mins by Kinobead based pull down assay	kd	0.0610	uM
2-amino-N-[1-[8-chloro-1-cyano-5-(2-methyl-1,1-dioxo-1,4-thiazinan-4-yl)imidazo[1,5-a]pyridin-6-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	2066696: Inhibition of Ribosomal protein S6 kinase in human THP-1 cells by ELISA analysis	ic50	0.3000	uM
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-4-(triazolo[4,5-b]pyridin-3-yl)benzamide	1585498: Binding affinity to 80S ribosome in human HuH7 cells expressing human C-terminal V5/6-His-tagged PCSK9 assessed as inhibition of PCSK9 secretion after 16 to 24 hrs by AlphaLISA method	ic50	0.3000	uM
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-3-[4-(triazolo[4,5-b]pyridin-3-yl)phenyl]propanamide	1532845: Binding affinity to 80S ribosome in human HuH7 cells harboring human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.3800	uM
N-isoquinolin-1-yl-N-[(3R)-piperidin-3-yl]-4-(triazolo[4,5-b]pyridin-3-yl)benzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.3900	uM
N-(3-chloro-2-pyridinyl)-4-(6-methyltriazolo[4,5-b]pyridin-3-yl)-N-[(3R)-piperidin-3-yl]benzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.4100	uM
N-(3-chloro-2-pyridinyl)-4-(5-methyltriazolo[4,5-b]pyridin-3-yl)-N-[(3R)-piperidin-3-yl]benzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.4500	uM
N-(1-methylpyrrolo[2,3-c]pyridin-7-yl)-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	0.5000	uM
N-isoquinolin-1-yl-N-[(3R)-piperidin-3-yl]-4-pyrazolo[1,5-a]pyrimidin-3-ylbenzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.6900	uM
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-5-(triazolo[4,5-b]pyridin-3-yl)pyridine-2-carboxamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.7100	uM
N-(3-chloro-2-pyridinyl)-3-[5-(6-methyltriazolo[4,5-b]pyridin-3-yl)-2-pyridinyl]-N-[(3R)-piperidin-3-yl]propanamide	1532845: Binding affinity to 80S ribosome in human HuH7 cells harboring human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.8500	uM
N-(3-chloro-2-pyridinyl)-5-(6-methyltriazolo[4,5-b]pyridin-3-yl)-N-[(3R)-piperidin-3-yl]pyridine-2-carboxamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.8500	uM
N-(3-methyl-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-4-pyrazolo[1,5-a]pyrimidin-3-ylpiperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	0.9200	uM
N-isoquinolin-1-yl-4-(1-methylpyrazol-4-yl)-N-[(3R)-piperidin-3-yl]benzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	1.0600	uM
N-isoquinolin-1-yl-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	1.5400	uM
N-(3-methyl-2-pyridinyl)-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532845: Binding affinity to 80S ribosome in human HuH7 cells harboring human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	2.0500	uM
N-(3-chloro-2-pyridinyl)-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	2.0800	uM
N-(5,8-dihydroisoquinolin-1-yl)-3-(4-methoxyphenyl)-N-[(3R)-piperidin-3-yl]propanamide	1584424: Inhibition of human 80S ribosome-mediated PCSK9 translation expressed in CHO-K1 cells assessed as reduction in PCSK9 secretion	ec50	2.2000	uM
N-isoquinolin-1-yl-3-(4-methoxyphenyl)-N-[(3R)-piperidin-3-yl]propanamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	2.6300	uM
N-(3-chloro-2-pyridinyl)-4-(6-methylpyrazin-2-yl)-N-[(3R)-piperidin-3-yl]benzamide	1497963: Binding affinity to 80S ribosome in human HuH7 cells assessed as inhibition of PCSK9 mRNA translation after overnight incubation by ELISA	ic50	2.8200	uM
N-(3-chloro-2-pyridinyl)-4-[6-(dimethylamino)pyrazin-2-yl]-N-[(3R)-piperidin-3-yl]benzamide	1497963: Binding affinity to 80S ribosome in human HuH7 cells assessed as inhibition of PCSK9 mRNA translation after overnight incubation by ELISA	ic50	2.9700	uM
N-(3-chloro-2-pyridinyl)-4-[6-(methylamino)pyrazin-2-yl]-N-[(3R)-piperidin-3-yl]benzamide	1497963: Binding affinity to 80S ribosome in human HuH7 cells assessed as inhibition of PCSK9 mRNA translation after overnight incubation by ELISA	ic50	3.0800	uM
N-isoquinolin-1-yl-4-(6-methyl-1,2-benzoxazol-3-yl)-N-[(3R)-piperidin-3-yl]piperazine-1-carboxamide	1532845: Binding affinity to 80S ribosome in human HuH7 cells harboring human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	3.5000	uM
N-(3-methylpyrazin-2-yl)-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	3.6300	uM
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-6-(triazolo[4,5-b]pyridin-3-yl)pyridine-3-carboxamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	4.1000	uM
N-isoquinolin-1-yl-N-[(3R)-piperidin-3-yl]-4-pyrazin-2-ylbenzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	4.3000	uM
4-(2-fluorophenyl)-N-(3-methyl-2-pyridinyl)-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	4.3800	uM
2,2-dichloro-N-[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl]acetamide;sulfuric acid	717551: Inhibition of mitochondrial ribosome-mediated protein synthesis in human HeLa cells assessed as {35S]methionine incorporation by autoradiography	ic50	7.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Sirolimus	decreases expression, affects cotreatment, decreases phosphorylation, decreases reaction, affects binding (+4 more)	31
Resveratrol	affects cotreatment, increases phosphorylation, decreases expression, increases activity, decreases phosphorylation (+3 more)	13
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases reaction, affects binding, decreases reaction, increases phosphorylation, decreases phosphorylation	9
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases phosphorylation, increases reaction, increases response to substance, affects cotreatment, affects response to substance (+2 more)	9
bisphenol A	affects cotreatment, affects expression, decreases expression, increases expression, increases phosphorylation (+1 more)	7
Everolimus	decreases reaction, increases phosphorylation, decreases phosphorylation, affects cotreatment	7
dactolisib	decreases phosphorylation, increases reaction	6
Curcumin	decreases phosphorylation, decreases reaction, increases expression, increases phosphorylation, decreases expression	4
temsirolimus	decreases phosphorylation, decreases reaction, increases phosphorylation, increases reaction	3
mirdametinib	decreases phosphorylation, increases reaction	3
Arsenic Trioxide	decreases reaction, increases phosphorylation, decreases expression, affects cotreatment, decreases phosphorylation	3
Estradiol	increases expression, increases reaction, decreases reaction, increases phosphorylation	3
Particulate Matter	increases expression, increases phosphorylation	3
ON123300	decreases phosphorylation	2
bisphenol F	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	affects binding, increases reaction, decreases expression, increases activity	2
ochratoxin A	increases phosphorylation	2
deguelin	decreases expression, decreases phosphorylation	2
tanespimycin	decreases expression, decreases phosphorylation	2
bardoxolone methyl	decreases reaction, increases phosphorylation, decreases expression	2
dorsomorphin	decreases phosphorylation, decreases reaction, increases phosphorylation	2
Ku 0063794	affects cotreatment, decreases phosphorylation	2
bisphenol S	increases expression, affects cotreatment, decreases expression	2
NVP-BKM120	decreases phosphorylation, increases reaction	2
capivasertib	decreases phosphorylation	2
vistusertib	decreases phosphorylation	2
Imatinib Mesylate	decreases phosphorylation, affects cotreatment	2
Erlotinib Hydrochloride	decreases expression, decreases phosphorylation, decreases reaction	2
Dasatinib	decreases phosphorylation	2
Wortmannin	affects binding, decreases reaction, increases activity, increases phosphorylation, affects cotreatment	2

ChEMBL screening assays

108 unique, capped per target: 108 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3371387	Binding	Inhibition of S6 ribosomal protein phosphorylation in human A549 cells at 250 to 500 uM after 6 hrs by Western blotting analysis	The identification of perillyl alcohol glycosides with improved antiproliferative activity. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07287202	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety, Tolerability, and Pharmacokinetics of SVG103 (Paxalisib) in Focal Cortical Dysplasia Type II (FCD-II), Tuberous Sclerosis Complex (TSC) or Hemimegalencephaly (HME)
NCT04344626	Not specified	WITHDRAWN	Use of a Tonometer to Identify Epileptogenic Lesions During Pediatric Epilepsy Surgery