RPS6KA1

Summary

RPS6KA1 (ribosomal protein S6 kinase A1, HGNC:10430) is a protein-coding gene on chromosome 1p36.11, encoding Ribosomal protein S6 kinase alpha-1 (Q15418). Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and….

This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 nonidentical 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. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 6195 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 117 total
• Druggable target: yes — 37 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002953

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10430
Approved symbol	RPS6KA1
Name	ribosomal protein S6 kinase A1
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	RSK1, HU-1, p90Rsk, MAPKAPK1
Ensembl gene	ENSG00000117676
Ensembl biotype	protein_coding
OMIM	601684
Entrez	6195

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 11 protein_coding, 7 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000366866, ENST00000374163, ENST00000374166, ENST00000374168, ENST00000403732, ENST00000438977, ENST00000474934, ENST00000488985, ENST00000524436, ENST00000525525, ENST00000525582, ENST00000526040, ENST00000526792, ENST00000527264, ENST00000529454, ENST00000530003, ENST00000530305, ENST00000530607, ENST00000531113, ENST00000531382, ENST00000892920, ENST00000952527, ENST00000952528

RefSeq mRNA: 3 — MANE Select: NM_002953 NM_001006665, NM_001330441, NM_002953

CCDS: CCDS284, CCDS30649, CCDS81286

Canonical transcript exons

ENST00000374168 — 22 exons

Exon	Start	End
ENSE00001951242	26574079	26575025
ENSE00002171940	26529761	26529983
ENSE00003470424	26556654	26556718
ENSE00003471820	26561505	26561663
ENSE00003486086	26547189	26547270
ENSE00003488069	26573224	26573361
ENSE00003499674	26555151	26555221
ENSE00003507535	26556998	26557100
ENSE00003507729	26555537	26555625
ENSE00003521520	26561045	26561134
ENSE00003529141	26571849	26571925
ENSE00003533361	26572176	26572293
ENSE00003553031	26546867	26546983
ENSE00003557941	26553391	26553497
ENSE00003562371	26551644	26551723
ENSE00003563498	26554596	26554738
ENSE00003564726	26558807	26558937
ENSE00003573880	26560726	26560851
ENSE00003583645	26571449	26571610
ENSE00003630393	26551397	26551477
ENSE00003658122	26536925	26536969
ENSE00003788383	26554214	26554251

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.0638 / max 653.5042, expressed in 1535 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1635	13.4456	485
1627	10.4233	1504
1630	0.8469	280
1634	0.6920	295
201421	0.3198	109
1629	0.2870	67
1631	0.0490	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	98.67	gold quality
granulocyte	CL:0000094	98.41	gold quality
mucosa of transverse colon	UBERON:0004991	96.99	gold quality
leukocyte	CL:0000738	96.62	gold quality
monocyte	CL:0000576	96.50	gold quality
duodenum	UBERON:0002114	96.14	gold quality
spleen	UBERON:0002106	95.16	gold quality
lymph node	UBERON:0000029	94.32	gold quality
vermiform appendix	UBERON:0001154	93.97	gold quality
rectum	UBERON:0001052	93.77	gold quality
bone marrow	UBERON:0002371	93.61	gold quality
upper lobe of left lung	UBERON:0008952	93.50	gold quality
right lung	UBERON:0002167	92.54	gold quality
bone marrow cell	CL:0002092	92.47	gold quality
tonsil	UBERON:0002372	92.43	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.07	gold quality
small intestine	UBERON:0002108	91.94	gold quality
lung	UBERON:0002048	91.85	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.82	gold quality
right lobe of thyroid gland	UBERON:0001119	91.60	gold quality
left lobe of thyroid gland	UBERON:0001120	90.74	gold quality
transverse colon	UBERON:0001157	90.61	gold quality
thyroid gland	UBERON:0002046	90.46	gold quality
adult mammalian kidney	UBERON:0000082	90.22	gold quality
metanephros cortex	UBERON:0010533	90.04	gold quality
right uterine tube	UBERON:0001302	89.99	gold quality
cerebellum	UBERON:0002037	89.80	gold quality
cerebellar cortex	UBERON:0002129	89.79	gold quality
cerebellar hemisphere	UBERON:0002245	89.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.99	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.54
E-MTAB-5061	no	3.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, EGR1, NR4A1, YBX1

miRNA regulators (miRDB)

52 targeting RPS6KA1, 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-4713-3P	100.00	65.92	505
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-939-3P	98.97	65.07	2347

Literature-anchored findings (GeneRIF, showing 40)

• was found to be activated by lead in a PKC- and MAPK-dependent manner (PMID:11861786)
• Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site. (PMID:11914378)
• TF cytoplasmic domain-independent stimulation of protein synthesis via activation of S6 kinase contributes to FVIIa effects in pathophysiology. (PMID:12019261)
• activated transiently by stromal cell-derived factor 1 alpha alone or synergistically in combination with other cytokines (PMID:12036856)
• Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E (PMID:12080086)
• RSK1 is negatively regulated by 14-3-3beta (PMID:12618428)
• overexpressed in breast tumors (PMID:15112576)
• Results suggest that active fibroblast growth factor receptor 1 kinase regulates the functions of nuclear 90-kDa ribosomal S6 kinase. (PMID:15117958)
• that p90 ribosomal S 6 protein kinase 1 (RSK1) mediates the PGE2-induced phosphorylation of cAMP-response element binding protein (PMID:15615708)
• monitored 14 previously uncharacterized and six known phosphorylation events after phorbol ester stimulation in the ERK/p90 ribosomal S6 kinase-signaling targets, TSC1 and TSC2, and a protein kinase C-dependent pathway to TSC2 phosphorylation (PMID:15647351)
• S6 kinase 1 is a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase (PMID:15905173)
• RSK-mediated phosphorylation of DAPK is a unique mechanism for suppressing the proapoptotic function of this death kinase in healthy cells as well as Ras/Raf-transformed cells. (PMID:16213824)
• interactions between subunits of PKA and RSK1 that are dependent upon the activation state of RSK1 and determine its subcellular distribution and biological actions (PMID:16738324)
• A study evaluating the impact of carbohydrate and/or protein ingestion before and after exercise on ribosomal protein S6 kinase (S6K1) and S6 phosphorylation status in human skeletal muscle tissue is presented. (PMID:17634259)
• study reports the crystal structures of the unactivated RSK1 N-terminal kinase domain bound to different ligands at 2.0 A resolution (PMID:17965187)
• Residues 411-735 of human RSK1, covering the C-terminal serine/threonine kinase catalytic domain and the functionally important tail, were cloned into an Escherichia coli expression vector (PMID:18084084)
• The ERK-RSK1 activation by growth factors delays G2/M transition and this might be required to maintain genomic integrity during growth factor stimulation. (PMID:18450423)
• RSK1 and RSK2 are required for Raptor phosphorylation in vivo and directly phosphorylate Raptor in vitro. (PMID:18722121)
• betaTrCP promotes cell survival in cooperation with the ERK-RSK pathway by targeting BimEL for degradation. (PMID:19150432)
• The chaperonin CCT is identified as a novel physiological substrate for p90 ribosomal S6 kinase (RSK) and p70 ribosomal S6 kinase (S6K). (PMID:19332537)
• Increased motility of cancer cells with PI3K and/or MAPK pathway activation may result partly from RSK1 activation, accumulation of p27T198 in the cytoplasm, p27:RhoA binding, inhibition of RhoA/Rock pathway activation, and loss of actomyosin stability. (PMID:19470470)
• RSK phosphorylates Nur77 at serine 354, which modulates Nur77 nuclear export and intracellular translocation during T cell death. (PMID:19675165)
• RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells. (PMID:19716794)
• Findings demonstrate that interactions between endogenous RSK1 and PKAc in intact cells regulate the ability of cAMP to activate PKA and identify a novel mechanism by which PKA activity is regulated by the Erk1/2 pathway. (PMID:19808666)
• Data show that RSK1 regulates PKAc activity in a cAMP-independent manner, and PKARIalpha by associating with RSK1 regulates its activation and its biological functions. (PMID:20048145)
• p22(phox)-based Nox oxidases maintain HIF-2alpha protein expression through inactivation of tuberin and downstream activation of ribosomal protein S6 kinase 1/4E-BP1 pathway (PMID:20304964)
• This review discusses the different characteristics of regulating the activity and subcellular localization of MK5 and RSK1 by PKA and the functional implications of these interactions. (PMID:20849292)
• 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)
• small molecules such as celecoxib induce DR5 expression through activating ERK/RSK signaling and subsequent Elk1 activation and ATF4-dependent CHOP induction (PMID:21044953)
• our data provide evidence for a critical role for the activated RSK1 in IFNlambda signaling (PMID:21075852)
• Data show that VASP and Mena interact with RSK1. (PMID:21423205)
• Data show that SH3P2 was phosphorylated on Ser(202) by ribosomal S6 kinase (RSK) in an ERK pathway-dependent manner, and such phosphorylation inhibited the ability of SH3P2 to suppress cell motility. (PMID:21501342)
• PGD(2) can induce MUC5B overproduction via ERK MAPK/RSK1/CREB signaling and that DP1 receptor may have suppressive effects in controlling MUC5B overproduction in the airway. (PMID:21832046)
• Type I keratin 17 protein is phosphorylated on serine 44 by p90 ribosomal protein S6 kinase 1 (RSK1) in a growth- and stress-dependent fashion (PMID:22006917)
• the results highlight a novel role for RSK1/2 and HSP27 phosphoproteins in P. aeruginosa-dependent induction of transcription of the IL-8 gene in human bronchial epithelial cells. (PMID:22031759)
• melatonin enhances cisplatin-induced apoptosis via the inactivation of ERK/p90RSK/HSP27 cascade (PMID:22050627)
• Collectively, these results identify a novel locus of apoptosomal regulation wherein MAPK signalling promotes Rsk-catalysed Apaf-1 phosphorylation and consequent binding of 14-3-3varepsilon, resulting in decreased cellular responsiveness to cytochrome c. (PMID:22246185)
• Resistance to trastuzumab was observed in tumor cells with elevated MNK1 expression, furthermore, inhibition of RSK1 restored sensitivity to resistant cells. (PMID:22249268)
• results suggest p90 RSK facilitates nuclear Chk1 accumulation through Chk1-Ser-280 phosphorylation and that this pathway plays an important role in the preparation for monitoring genetic stability during cell proliferation. (PMID:22357623)
• Data indicate that Plk1 siRNA interference and overexpression increased phosphorylation of RSK1, suggesting that Plk1 inhibits RSK1. (PMID:22427657)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	rps6ka1	ENSDARG00000033437
mus_musculus	Rps6ka1	ENSMUSG00000003644
rattus_norvegicus	Rps6ka1	ENSRNOG00000042411
drosophila_melanogaster	JIL-1	FBGN0020412
drosophila_melanogaster	S6k	FBGN0283472
caenorhabditis_elegans	rskn-2	WBGENE00008311
caenorhabditis_elegans		WBGENE00012929
caenorhabditis_elegans		WBGENE00017898
caenorhabditis_elegans		WBGENE00044281

Paralogs (7): RPS6KA2 (ENSG00000071242), RPS6KA6 (ENSG00000072133), RPS6KA5 (ENSG00000100784), RPS6KB1 (ENSG00000108443), RPS6KA4 (ENSG00000162302), RPS6KB2 (ENSG00000175634), RPS6KA3 (ENSG00000177189)

Protein

Protein identifiers

Ribosomal protein S6 kinase alpha-1 — Q15418 (reviewed: Q15418)

Alternative names: 90 kDa ribosomal protein S6 kinase 1, MAP kinase-activated protein kinase 1a, Ribosomal S6 kinase 1

All UniProt accessions (9): A6NND1, Q15418, E9PAN7, E9PGT3, E9PMM7, E9PPC1, E9PPN6, Q5SVM6, Q5SVM7

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1, which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at ‘Ser-9’ and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the pre-initiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at ‘Ser-1798’, which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Also involved in feedback regulation of mTORC1 and mTORC2 by phosphorylating DEPTOR. Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Mediates induction of hepatocyte prolifration by TGFA through phosphorylation of CEBPB. Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. Phosphorylates EPHA2 at ‘Ser-897’, the RPS6KA-EPHA2 signaling pathway controls cell migration. In response to mTORC1 activation, phosphorylates EIF4B at ‘Ser-406’ and ‘Ser-422’ which stimulates bicarbonate cotransporter SLC4A7 mRNA translation, increasing SLC4A7 protein abundance and function. (Microbial infection) Promotes the late transcription and translation of viral lytic genes during Kaposi’s sarcoma-associated herpesvirus/HHV-8 infection, when constitutively activated.

Subunit / interactions. Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation. Interacts with ETV1/ER81 and FGFR1. (Microbial infection) Interacts with Kaposi’s sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction allows RPS6KA1 activation.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Activated by phosphorylation at Ser-221 by PDPK1. Autophosphorylated on Ser-380, as part of the activation process. May be phosphorylated at Thr-359 and Ser-363 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-573 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-380, allowing binding of PDPK1, which in turn phosphorylates Ser-221 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 (4)

UniProt ID	Names	Canonical?
Q15418-1	1	yes
Q15418-2	2
Q15418-3	3
Q15418-4	4

RefSeq proteins (3): NP_001006666, NP_001317370, NP_002944* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000961	AGC-kinase_C	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016239	Ribosomal_S6_kinase_II	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR017892	Pkinase_C	Domain
IPR041906	RSK_N	Domain

Pfam: PF00069, PF00433

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (78 total): helix 28, strand 21, modified residue 9, turn 4, binding site 4, domain 3, splice variant 3, sequence conflict 2, active site 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
5V62	X-RAY DIFFRACTION	1.9
7P74	X-RAY DIFFRACTION	1.9
2Z7Q	X-RAY DIFFRACTION	2
2Z7R	X-RAY DIFFRACTION	2
2Z7S	X-RAY DIFFRACTION	2.1
5CSI	X-RAY DIFFRACTION	2.13
4NIF	X-RAY DIFFRACTION	2.15
5V61	X-RAY DIFFRACTION	2.2
4H3P	X-RAY DIFFRACTION	2.3
5N7D	X-RAY DIFFRACTION	2.3
5N7F	X-RAY DIFFRACTION	2.3
6TWY	X-RAY DIFFRACTION	2.3
2WNT	X-RAY DIFFRACTION	2.4
5CSF	X-RAY DIFFRACTION	2.4
3TEI	X-RAY DIFFRACTION	2.4
7QQL	X-RAY DIFFRACTION	2.44
7PC8	X-RAY DIFFRACTION	2.5
8XOV	X-RAY DIFFRACTION	2.55
8WF4	X-RAY DIFFRACTION	2.65
3RNY	X-RAY DIFFRACTION	2.7
5CSJ	X-RAY DIFFRACTION	2.7
5CSN	X-RAY DIFFRACTION	2.95
5N7G	X-RAY DIFFRACTION	2.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15418-F1	77.30	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): 187 (proton acceptor); 535 (proton acceptor)

Ligand- & substrate-binding residues (4): 68–76; 94; 424–432; 447

Post-translational modifications (9): 54, 221, 307, 359, 363, 369, 380, 573, 732

Function

Pathways and Gene Ontology

Reactome pathways

52 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-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
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)

MSigDB gene sets: 337 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, KEGG_MAPK_SIGNALING_PATHWAY, MODULE_45, GOBP_GROWTH, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, MODULE_16, CACCAGC_MIR138, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_CELL_CELL_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (15): regulation of DNA-templated transcription (GO:0006355), protein phosphorylation (GO:0006468), signal transduction (GO:0007165), chemical synaptic transmission (GO:0007268), positive regulation of cell growth (GO:0030307), negative regulation of TOR signaling (GO:0032007), TORC1 signaling (GO:0038202), negative regulation of apoptotic process (GO:0043066), regulation of translation in response to stress (GO:0043555), positive regulation of cell differentiation (GO:0045597), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), hepatocyte proliferation (GO:0072574), positive regulation of hepatic stellate cell activation (GO:2000491), intracellular signal transduction (GO:0035556)

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

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Toll-like Receptor Cascades	3
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
MITF-M-regulated melanocyte development	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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	3
cellular anatomical structure	3
DNA-templated transcription	2
positive regulation of cellular process	2
TOR signaling	2
intracellular anatomical structure	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
anterograde trans-synaptic signaling	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
translation	1
regulation of translation	1
cellular response to stress	1
cell differentiation	1
regulation of cell differentiation	1
positive regulation of developmental process	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
epithelial cell proliferation	1
hepatic stellate cell activation	1
positive regulation of cell activation	1
regulation of hepatic stellate cell activation	1
signal transduction	1

Protein interactions and networks

STRING

2110 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPS6KA1	MAPK1	P28482	821
RPS6KA1	RPTOR	Q8N122	798
RPS6KA1	CREB1	P16220	783
RPS6KA1	TSC2	P49815	776
RPS6KA1	S100B	P04271	758
RPS6KA1	RICTOR	Q6R327	752
RPS6KA1	FOS	P01100	727
RPS6KA1	MTOR	P42345	711
RPS6KA1	RPS6	P08227	709
RPS6KA1	EIF4EBP1	Q13541	708
RPS6KA1	FGFR1	P11362	703
RPS6KA1	CREBBP	Q92793	697
RPS6KA1	PKN2	Q16513	669
RPS6KA1	IRS1	P35568	664
RPS6KA1	RHEB	Q15382	630

IntAct

417 interactions, top by confidence:

A	B	Type	Score
MAPK1	RPS6KA1	psi-mi:“MI:2364”(proximity)	0.900
MAPK1	RPS6KA1	psi-mi:“MI:0915”(physical association)	0.900
RPS6KA1	MAPK1	psi-mi:“MI:0407”(direct interaction)	0.900
FYN	HSP90AA1	psi-mi:“MI:0914”(association)	0.800
RPS6KA1	RPS6KA3	psi-mi:“MI:0914”(association)	0.790
MAPK1	MAPK3	psi-mi:“MI:0914”(association)	0.770
SCRIB	RPS6KA1	psi-mi:“MI:0407”(direct interaction)	0.760
RPS6KA1	SCRIB	psi-mi:“MI:0915”(physical association)	0.760
RPS6KA1	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.760
RPS6KA1	CDC37	psi-mi:“MI:0915”(physical association)	0.740
TRRAP	ATXN7	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSP90AB1	RPS6KA1	psi-mi:“MI:0915”(physical association)	0.670
MAGI1	RPS6KA1	psi-mi:“MI:0407”(direct interaction)	0.650
RPS6KA2	RPS6KA3	psi-mi:“MI:0914”(association)	0.640
MAPK1	DHPS	psi-mi:“MI:0914”(association)	0.640
RPS6KA3	ROCK2	psi-mi:“MI:0914”(association)	0.640

BioGRID (306): POLDIP3 (Biochemical Activity), POLDIP3 (Reconstituted Complex), RPS6KA1 (Affinity Capture-Western), RPS6KA1 (Affinity Capture-Western), DLC1 (Biochemical Activity), ILKAP (Co-fractionation), RPS6KA1 (Affinity Capture-MS), RPS6KA1 (Proximity Label-MS), RPS6KA1 (Affinity Capture-MS), DEPTOR (Biochemical Activity), MAPK1 (Reconstituted Complex), RPS6KA1 (Two-hybrid), RPS6KA1 (Affinity Capture-Western), FGFR1 (Affinity Capture-Western), UBE2T (Biochemical Activity)

ESM2 similar proteins: A7MB74, A8XJQ6, A8XNJ6, O00141, O55173, O75582, P05986, P10665, P10666, P18652, P18653, P18654, P21901, P51812, Q02111, Q04759, Q05655, Q06226, Q12706, Q15349, Q15418, Q2PJ68, Q4R633, Q5BKK4, Q5F3L1, Q5PU49, Q5Q0U5, Q5R4K3, Q5R7A7, Q63531, Q6GLY8, Q6GPN6, Q6PFQ0, Q6U1I9, Q7JP68, Q7TPS0, Q7ZTW4, Q8C050, Q8R4U9, Q8R4V0

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

94 interactions.

A	Effect	B	Mechanism
MAPK1	“up-regulates activity”	RPS6KA1	phosphorylation
MAPK3	“up-regulates activity”	RPS6KA1	phosphorylation
RPS6KA1	“down-regulates activity”	EEF2K	phosphorylation
RPS6KA1	down-regulates	GSK3B	phosphorylation
RPS6KA1	“down-regulates activity”	H3-3A	phosphorylation
RPS6KA1	up-regulates	FLNA	phosphorylation
RPS6KA1	up-regulates	EIF4B	phosphorylation
TP53	up-regulates	RPS6KA1
RPS6KA1	down-regulates	TSC2	phosphorylation
RPS6KA1	down-regulates	METTL1	phosphorylation
RPS6KA1	unknown	CARHSP1	phosphorylation
RPS6KA1	up-regulates	RPS6	phosphorylation
RPS6KA1	“down-regulates activity”	BAD	phosphorylation
RPS6KA1	unknown	RANBP3	phosphorylation
RPS6KA1	“up-regulates activity”	RPS6KA1	phosphorylation
RPS6KA1	down-regulates	CIC	phosphorylation
RPS6KA1	down-regulates	VASP	phosphorylation
RPS6KA1	up-regulates	CCT2	phosphorylation
RPS6KA1	down-regulates	MITF	phosphorylation
RPS6KA1	“down-regulates quantity by destabilization”	IRS1	phosphorylation
RPS6KA1	down-regulates	DEPTOR	phosphorylation
RPS6KA1	down-regulates	MXD1	phosphorylation
RPS6KA1	up-regulates	RPTOR	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nuclear Events (kinase and transcription factor activation)	5	21.1×	1e-04
MAP kinase activation	5	18.8×	1e-04
Toll Like Receptor 10 (TLR10) Cascade	6	15.8×	1e-04
Toll Like Receptor 5 (TLR5) Cascade	6	15.8×	1e-04
Interleukin-17 signaling	5	15.5×	3e-04
Toll Like Receptor TLR6:TLR2 Cascade	7	15.0×	8e-05
MyD88 cascade initiated on plasma membrane	6	14.9×	1e-04
Toll Like Receptor 2 (TLR2) Cascade	7	14.8×	8e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein phosphorylation	10	6.0×	3e-03
intracellular signal transduction	15	5.1×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3528 predictions. Top by Δscore:

Variant	Effect	Δscore
1:26529980:GGAG:G	donor_gain	1.0000
1:26529981:GAG:G	donor_gain	1.0000
1:26529981:GAGG:G	donor_gain	1.0000
1:26529983:GGT:G	donor_loss	1.0000
1:26529984:G:GG	donor_gain	1.0000
1:26529985:T:G	donor_loss	1.0000
1:26536967:AAGGT:A	donor_loss	1.0000
1:26536969:GGTG:G	donor_loss	1.0000
1:26536970:GTG:G	donor_loss	1.0000
1:26546984:G:GG	donor_gain	1.0000
1:26547267:AAAGG:A	donor_loss	1.0000
1:26547270:GGTG:G	donor_loss	1.0000
1:26547271:G:C	donor_loss	1.0000
1:26551390:T:TA	acceptor_gain	1.0000
1:26551395:A:AG	acceptor_gain	1.0000
1:26551396:G:GA	acceptor_gain	1.0000
1:26551396:GTAC:G	acceptor_gain	1.0000
1:26551639:CCCA:C	acceptor_loss	1.0000
1:26551641:CAG:C	acceptor_loss	1.0000
1:26551642:A:AG	acceptor_gain	1.0000
1:26551643:G:GA	acceptor_gain	1.0000
1:26551643:GC:G	acceptor_gain	1.0000
1:26551643:GCC:G	acceptor_gain	1.0000
1:26551721:GAG:G	donor_gain	1.0000
1:26553386:T:A	acceptor_gain	1.0000
1:26553388:CAG:C	acceptor_loss	1.0000
1:26553389:A:AG	acceptor_gain	1.0000
1:26553389:AG:A	acceptor_gain	1.0000
1:26553389:AGGT:A	acceptor_gain	1.0000
1:26553390:G:GA	acceptor_gain	1.0000

AlphaMissense

4808 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:26546943:T:C	F62S	1.000
1:26546963:G:C	G69R	1.000
1:26546964:G:A	G69D	1.000
1:26546964:G:T	G69V	1.000
1:26546969:G:A	G71R	1.000
1:26546969:G:C	G71R	1.000
1:26546970:G:A	G71E	1.000
1:26546975:T:A	F73I	1.000
1:26546975:T:C	F73L	1.000
1:26546977:T:A	F73L	1.000
1:26546977:T:G	F73L	1.000
1:26546978:G:C	G74R	1.000
1:26546979:G:A	G74D	1.000
1:26546979:G:T	G74V	1.000
1:26547196:T:C	L78P	1.000
1:26547238:C:A	A92D	1.000
1:26547243:A:C	K94Q	1.000
1:26547243:A:G	K94E	1.000
1:26547245:G:C	K94N	1.000
1:26547245:G:T	K94N	1.000
1:26547250:T:C	L96P	1.000
1:26547257:G:C	K98N	1.000
1:26547257:G:T	K98N	1.000
1:26551423:G:A	E112K	1.000
1:26551424:A:T	E112V	1.000
1:26551428:A:C	R113S	1.000
1:26551428:A:T	R113S	1.000
1:26551436:T:A	L116Q	1.000
1:26551436:T:C	L116P	1.000
1:26551646:T:C	F131L	1.000

dbSNP variants (sampled 300 via entrez): RS1000154962 (1:26572799 C>T), RS1000182243 (1:26539898 A>G), RS1000192747 (1:26559141 C>T), RS1000258094 (1:26545429 G>T), RS1000264376 (1:26533610 CAGA>C), RS1000297845 (1:26564186 C>T), RS1000387987 (1:26527964 A>G), RS1000458831 (1:26570439 A>C), RS1000570911 (1:26556047 G>C), RS1000639672 (1:26562805 C>T), RS1000698353 (1:26533335 GC>G), RS1000766896 (1:26568441 G>C), RS1000797159 (1:26545920 C>A,T), RS1000829758 (1:26570139 G>A,T), RS1000829923 (1:26551227 G>T)

Disease associations

OMIM: gene MIM:601684 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002337_67	Amyotrophic lateral sclerosis (sporadic)	1.000000e-06
GCST002726_64	Glucose homeostasis traits	6.000000e-06
GCST004602_7	Mean corpuscular volume	2.000000e-10
GCST005790_76	Rosacea symptom severity	2.000000e-06
GCST005790_77	Rosacea symptom severity	1.000000e-06
GCST006436_1	Triglyceride levels	7.000000e-11
GCST009864_1	Fasting plasma glucose	6.000000e-11
GCST90002388_645	Lymphocyte count	8.000000e-13
GCST90002396_121	Mean reticulocyte volume	1.000000e-15
GCST90002397_621	Mean spheric corpuscular volume	4.000000e-34
GCST90002407_390	White blood cell count	2.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006830	insulin metabolic clearance rate measurement
EFO:0009180	rosacea severity measurement
EFO:0004530	triglyceride measurement
EFO:0004587	lymphocyte count
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2553 (SINGLE PROTEIN), CHEMBL3832633 (PROTEIN FAMILY), CHEMBL4106179 (PROTEIN FAMILY), CHEMBL4523616 (PROTEIN FAMILY), CHEMBL4630724 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

37 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 238,502 (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
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL274654	ORANTINIB	3	3,596
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL1721885	SU-014813	2
CHEMBL1738757	REBASTINIB	2
CHEMBL230011	TG100-115	2
CHEMBL3137336	UPROSERTIB	2
CHEMBL31574	FISETIN	2
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2
CHEMBL513909	BI-2536	2
CHEMBL572878	TOZASERTIB	2
CHEMBL1908397	KW-2449	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 (7 total), top 7:

Ligand	Action	Affinity	Parameter
prexasertib	Inhibition	8.05	pIC50
BI-D1870	Inhibition	7.51	pIC50
compound E22 [PMID: 31298542]	Inhibition	6.88	pIC50
dorsomorphin	Inhibition	6.68	pIC50
compound 33 [PMID: 19364658]	Inhibition	6.54	pIC50
GSK429286A	Inhibition	6.11	pIC50
GSK-1838705A	Inhibition	5.8	pIC50

Binding affinities (BindingDB)

44 measured of 51 human assays (51 total across all organisms); most potent 44 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-7-[(2-methylpyrazol-3-yl)amino]-1,6-naphthyridine-2-carboxamide	IC50	0.748 nM	US-9388171: Serine/threonine kinase inhibitors
N-[(S)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-7-[[(2S)-1-hydroxypropan-2-yl]amino]-1,6-naphthyridine-2-carboxamide	IC50	1.15 nM	US-9388171: Serine/threonine kinase inhibitors
Staurosporine	KD	1.7 nM
N-[(S)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-7-(oxan-4-ylamino)-1,6-naphthyridine-2-carboxamide	IC50	1.86 nM	US-9388171: Serine/threonine kinase inhibitors
3-[2-(4-amino-1,2,5-oxadiazol-3-yl)-7-(3-aminopropoxy)-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]prop-2-yn-1-ol	IC50	2 nM
(R)¿N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide	IC50	2 nM	US-9771366: Substituted tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamides as RSK inhibitors
N-[(1R)-1-(3-fluoro-4-methoxyphenyl)propyl]-7-(oxan-4-ylamino)-1,6-naphthyridine-2-carboxamide	IC50	2.1 nM	US-9388171: Serine/threonine kinase inhibitors
N-[(S)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-3-[(2-methylpyrazol-3-yl)amino]isoquinoline-6-carboxamide	IC50	2.29 nM	US-9388171: Serine/threonine kinase inhibitors
N-[(1R)-1-(4-chloro-3-fluorophenyl)propyl]-3-(oxan-4-ylamino)isoquinoline-6-carboxamide	IC50	2.5 nM	US-9388171: Serine/threonine kinase inhibitors
3-[(2,5-dimethylpyrazol-3-yl)amino]-N-[(3S,4R)-4-(4-methoxyphenyl)-1-methylpyrrolidin-3-yl]isoquinoline-6-carboxamide	IC50	2.68 nM	US-9388171: Serine/threonine kinase inhibitors
N-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-3-(oxan-4-ylamino)isoquinoline-6-carboxamide	IC50	2.8 nM	US-9388171: Serine/threonine kinase inhibitors
N-[(4-chloro-3-fluorophenyl)methyl]-7-(oxan-4-ylamino)-1,6-naphthyridine-2-carboxamide	IC50	3.43 nM	US-9388171: Serine/threonine kinase inhibitors
(3R,4R)-3-methoxy-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	IC50	3.93 nM	US-10189849: CDK inhibitors
N-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-7-(oxan-4-ylamino)-1,6-naphthyridine-2-carboxamide	IC50	4.04 nM	US-9388171: Serine/threonine kinase inhibitors
3-[(2,5-dimethylpyrazol-3-yl)amino]-N-[(S)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]isoquinoline-6-carboxamide	IC50	4.6 nM	US-9388171: Serine/threonine kinase inhibitors
N-[2-(4-chloro-3-fluorophenyl)ethyl]-7-(oxan-4-ylamino)-1,6-naphthyridine-2-carboxamide	IC50	5.95 nM	US-9388171: Serine/threonine kinase inhibitors
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-7-(3-aminopropoxy)-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	IC50	6 nM
N-[(1R)-1-(4-chloro-3-fluorophenyl)propyl]-3-[(2,5-dimethylpyrazol-3-yl)amino]isoquinoline-6-carboxamide	IC50	6.5 nM	US-9388171: Serine/threonine kinase inhibitors
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole	KD	9.8 nM
4-[4-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazol-5-yl]pyridine	KD	12 nM
(1R)-1-[3-fluoro-4-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-6-yl)oxy]phenyl]ethanamine	IC50	13.9 nM	US-9493490: Boron-containing small molecules
N-[(4-fluoro-1H-indol-2-yl)methyl]-3-[[(2S)-1-hydroxypropan-2-yl]amino]isoquinoline-6-carboxamide	IC50	20.2 nM	US-9388171: Serine/threonine kinase inhibitors
(R)-1-benzyl-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3’,2’:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide	IC50	23.6 nM	US-9771366: Substituted tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamides as RSK inhibitors
4-[7-(3-aminopropoxy)-1-ethyl-4-(1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	IC50	32 nM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-7-(3-aminopropoxy)-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]but-3-yn-1-ol	IC50	50 nM
[3-chloro-4-[(1-hydroxy-7-propan-2-yl-3H-2,1-benzoxaborol-6-yl)oxy]phenyl]methanamine	IC50	59.6 nM	US-9493490: Boron-containing small molecules
4-[7-(3-aminopropoxy)-1-ethyl-4-(furan-3-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	IC50	79 nM
4-[7-(3-aminopropoxy)-4-(2-cyclopropylethynyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	IC50	79 nM
(r)-5,5-dimethyl-2-(phenylamino)-n-(1-phenylethyl)-5h-pyrrolo[3,4-d]pyrimidine-6(7h)-carboxamide	IC50	117 nM	US-9546173: Substituted pyrrolo[3,4-d]pyrimidines as kinase inhibitors
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
PKC-412	KD	190 nM
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-2-yl)-1H-imidazol-2-yl)benzamide	KD	190 nM
4-[7-(3-aminopropoxy)-1-ethyl-4-phenyl-1H-imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	IC50	331 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
4-[4-(3-aminoprop-1-yn-1-yl)-7-(3-aminopropoxy)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	IC50	794 nM
CI-1033	KD	1700 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM
(5,5-dimethyl-2-(phenylamino)-5h-pyrrolo[3,4-d]pyrimidin-6(7h)-yl)(4-methylpiperazin-1-yl)methanone	IC50	5570 nM	US-9546173: Substituted pyrrolo[3,4-d]pyrimidines as kinase inhibitors
(s)-n-(2-(dimethylamino)-1-phenylethyl)-5,5-dimethyl-2-(phenylamino)-5h-pyrrolo[3,4-d]pyrimidine-6(7h)-carboxamide	IC50	125000 nM	US-9546173: Substituted pyrrolo[3,4-d]pyrimidines as kinase inhibitors
(r)-n-(1-(dimethylamino)propan-2-yl)-5,5-dimethyl-2-(phenylamino)-5h-pyrrolo[3,4-d]pyrimidine-6(7h)-carboxamide	IC50	125000 nM	US-9546173: Substituted pyrrolo[3,4-d]pyrimidines as kinase inhibitors

ChEMBL bioactivities

268 potent at pChembl≥5 of 281 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.05	IC50	0.09	nM	STAUROSPORINE
9.93	IC50	0.118	nM	STAUROSPORINE
9.90	IC50	0.126	nM	STAUROSPORINE
9.72	IC50	0.19	nM	CHEMBL3683258
9.71	IC50	0.195	nM	CHEMBL5273774
9.52	IC50	0.3	nM	STAUROSPORINE
9.40	IC50	0.4	nM	CHEMBL5956719
9.30	IC50	0.5	nM	CHEMBL6009652
9.30	IC50	0.5	nM	CHEMBL5776408
9.22	IC50	0.6	nM	CHEMBL5988357
9.22	IC50	0.6	nM	CHEMBL5994226
9.15	IC50	0.7	nM	CHEMBL5979579
9.00	IC50	1	nM	CHEMBL523523
9.00	IC50	1	nM	CHEMBL5767678
9.00	IC50	1	nM	CHEMBL5749375
8.92	IC50	1.2	nM	STAUROSPORINE
8.85	IC50	1.4	nM	CHEMBL6008954
8.85	IC50	1.4	nM	CHEMBL5789687
8.80	IC50	1.6	nM	CHEMBL5878809
8.74	IC50	1.8	nM	CHEMBL5796741
8.72	IC50	1.9	nM	CHEMBL6032470
8.72	IC50	1.9	nM	CHEMBL5888865
8.70	IC50	2	nM	PF-03758309
8.70	IC50	2	nM	CHEMBL5811142
8.68	IC50	2.1	nM	CHEMBL5892762
8.60	IC50	2.5	nM	CHEMBL5797313
8.59	IC50	2.6	nM	CHEMBL5890153
8.57	IC50	2.7	nM	CHEMBL6021108
8.52	IC50	3	nM	CHEMBL573107
8.52	IC50	3	nM	CHEMBL5276100
8.48	IC50	3.3	nM	CHEMBL5864230
8.46	IC50	3.5	nM	CHEMBL5884975
8.44	IC50	3.62	nM	CHEMBL6002820
8.44	IC50	3.6	nM	CHEMBL5866601
8.42	IC50	3.79	nM	CHEMBL3909070
8.40	IC50	4	nM	CHEMBL5188373
8.40	IC50	4	nM	CHEMBL5790375
8.39	IC50	4.1	nM	CHEMBL5741074
8.32	IC50	4.8	nM	CHEMBL5891816
8.30	IC50	5	nM	CHEMBL3604794
8.30	Ki	5	nM	PF-03758309
8.30	IC50	5.01	nM	CHEMBL5290589
8.29	IC50	5.19	nM	CHEMBL5799297
8.27	IC50	5.4	nM	CHEMBL4062453
8.26	IC50	5.47	nM	CHEMBL3964006
8.24	IC50	5.8	nM	CHEMBL5740682
8.23	IC50	5.91	nM	CHEMBL573107
8.22	IC50	5.96	nM	CHEMBL4112587
8.22	IC50	6	nM	CHEMBL3604794
8.22	IC50	6	nM	CHEMBL3604793

PubChem BioAssay actives

204 with measured affinity, of 1990 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	1351000: Inhibition of RSK1 (unknown origin)	ic50	0.0001	uM
3-[2-(4-amino-1,2,5-oxadiazol-3-yl)-7-(3-aminopropoxy)-1-ethylimidazo[4,5-c]pyridin-4-yl]prop-2-yn-1-ol	1798494: In Vitro Kinase Inhibition Assay from Article 10.1021/jm8004527: “Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.”	ic50	0.0010	uM
1-[(3-hydroxyphenyl)methyl]-3-(4-pyridin-4-yl-1,3-thiazol-2-yl)urea;methanesulfonic acid	1119795: Inhibition of RSK1 (unknown origin)	ic50	0.0010	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	2168002: Inhibition of human RSK1 in presence of ATP	ic50	0.0020	uM
4’-[2-(4-amino-1,2,5-oxadiazol-3-yl)-5-fluorobenzimidazol-1-yl]-1-methyl-6-[(1-methyl-1,2,4-triazol-3-yl)methoxy]spiro[2-benzofuran-3,1’-cyclohexane]-1-ol	1933327: Inhibition of RSK1 (unknown origin)	ic50	0.0030	uM
2-(3,5-difluoro-4-hydroxyanilino)-5,7-dimethyl-8-(3-methylbutyl)-7H-pteridin-6-one	1662140: Inhibition of RSK1 (unknown origin)	ic50	0.0030	uM
5-bromo-4-N-(5-dimethylphosphoryl-2,3-dihydro-1,4-benzodioxin-6-yl)-2-N-[2-methoxy-4-[4-[3-(methoxymethyl)azetidin-1-yl]piperidin-1-yl]-5-methylphenyl]pyrimidine-2,4-diamine	1862884: Inhibition of RSK1 (unknown origin)	ic50	0.0040	uM
2,6-difluoro-4-[4-(4-morpholin-4-ylphenyl)-3-pyridinyl]phenol	1781665: Inhibition of full length recombinant His-tagged human RSK1 expressed in baculovirus expression system using biotin-labelled AGAGRSRHSSYPAGT-OH as substrate in presence of ATP	ic50	0.0050	uM
4-[7-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]imidazo[1,2-a]pyridin-3-yl]-2-[(3-fluorophenyl)methoxy]benzamide	1436379: Inhibition of RSK1 (unknown origin)	ic50	0.0054	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-7-(3-aminopropoxy)-1-ethylimidazo[4,5-c]pyridin-4-yl]but-3-yn-1-ol	1798494: In Vitro Kinase Inhibition Assay from Article 10.1021/jm8004527: “Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.”	ic50	0.0060	uM
2,6-difluoro-4-[4-[4-(4-methylpiperazin-1-yl)phenyl]-3-pyridinyl]phenol	1781665: Inhibition of full length recombinant His-tagged human RSK1 expressed in baculovirus expression system using biotin-labelled AGAGRSRHSSYPAGT-OH as substrate in presence of ATP	ic50	0.0060	uM
4-[7-(3-aminopropoxy)-1-ethyl-4-(1H-pyrrol-2-yl)imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	1798494: In Vitro Kinase Inhibition Assay from Article 10.1021/jm8004527: “Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.”	ic50	0.0130	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	1526160: Binding affinity to recombinant full length human N-terminal GST-tagged RPS6KA1 expressed in baculovirus expression system using S6K peptide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0160	uM
(5R)-4-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidin-1-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	1495043: Inhibition of human RSK1 measured at apparent ATP Km level	ic50	0.0200	uM
4-(1-ethylimidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine	1933327: Inhibition of RSK1 (unknown origin)	ic50	0.0240	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	624900: Binding constant for RSK1(Kin.Dom.1-N-terminal) kinase domain	kd	0.0280	uM
Brigatinib	2182814: Inhibition of human RPS6KA1 using KKLNRTLSVA as substrate in presence of [gamma33P]-ATP by HotSpot assay	ic50	0.0300	uM
5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)-N-[(3S,4S,6S)-4-(3,4-difluorophenyl)-6-(2-hydroxyethyl)piperidin-3-yl]furan-2-carboxamide	1608044: Inhibition of RSK1 (unknown origin) by mobility shift assay	ic50	0.0320	uM
[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethylimidazo[4,5-c]pyridin-7-yl]-[(3S)-3-aminopyrrolidin-1-yl]methanone	649970: Inhibition of RSK1	ic50	0.0350	uM
1-[(4R,7S)-12-chloro-14-fluoro-13-(2-fluoro-6-hydroxyphenyl)-4-methyl-10-oxa-2,5,16,18-tetrazatetracyclo[9.7.1.02,7.015,19]nonadeca-1(18),11,13,15(19),16-pentaen-5-yl]prop-2-en-1-one	1909582: Inhibition of p90RSK phosphorylation in human NCI-H358 cells harboring KRAS G12C mutant measured for 2 hrs by immunofluorescence assay	ic50	0.0360	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	1526160: Binding affinity to recombinant full length human N-terminal GST-tagged RPS6KA1 expressed in baculovirus expression system using S6K peptide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0360	uM
4-[7-(3-aminopropoxy)-1-ethyl-4-phenylimidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	1798494: In Vitro Kinase Inhibition Assay from Article 10.1021/jm8004527: “Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.”	ic50	0.0440	uM
N-(2-hydroxyethyl)-4-[3-[(Z)-(4-hydroxy-3-oxo-1-benzofuran-2-ylidene)methyl]-1-methylpyrrolo[2,3-b]pyridin-4-yl]benzamide	473518: Inhibition of RSK1	ic50	0.0459	uM
5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)-N-[(3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl]furan-2-carboxamide;(2R,3R)-2,3-dihydroxybutanedioic acid	1608044: Inhibition of RSK1 (unknown origin) by mobility shift assay	ic50	0.0480	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	676095: Inhibition of human Rsk1	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
4-[7-(3-aminopropoxy)-1-ethyl-4-(furan-3-yl)imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	1798494: In Vitro Kinase Inhibition Assay from Article 10.1021/jm8004527: “Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.”	ic50	0.0710	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	1823475: Inhibition of RSK1 (unknown origin) in human CAL-27 cells measured after 6 hrs by select screen kinase assay	ic50	0.0820	uM
(1S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)phenyl]ethanol	1953190: Inhibition of RSK1 (unknown origin)	ic50	0.0850	uM
[(2S,3S,4S,5R,6S)-4-acetyloxy-6-[5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxochromen-3-yl]oxy-5-hydroxy-2-methyloxan-3-yl] acetate	2008182: Inhibition of RSK1 (unknown origin)	ic50	0.0890	uM
N-(7-chloro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide	275215: Inhibition of RSK1	ic50	0.0900	uM
Sunitinib	508076: Binding affinity to RPS6KA4(Kin.Dom.1-N-terminal)	kd	0.0960	uM
2-[3-(methanesulfonamido)phenyl]-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,3-thiazol-2-yl]acetamide	1398932: Inhibition of p70S6K (unknown origin)	ki	0.1000	uM
3-(2,4-dichlorophenyl)-4-(1-methylindol-3-yl)pyrrole-2,5-dione	2008182: Inhibition of RSK1 (unknown origin)	ic50	0.1000	uM
3-(3-nitroso-1H-indol-2-yl)-1H-indol-2-ol	2008182: Inhibition of RSK1 (unknown origin)	ic50	0.1000	uM
Ruxolitinib	624901: Binding constant for RSK1(Kin.Dom.2-C-terminal) kinase domain	kd	0.1200	uM
5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)-N-[(3S,4S,6S)-4-(3,4-difluorophenyl)-6-[2-(methylamino)-2-oxoethyl]piperidin-3-yl]furan-2-carboxamide	1608044: Inhibition of RSK1 (unknown origin) by mobility shift assay	ic50	0.1310	uM
N-[3-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethylimidazo[4,5-c]pyridin-6-yl]oxyphenyl]-4-(2-morpholin-4-ylethoxy)benzamide	649970: Inhibition of RSK1	ic50	0.1320	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2168259: Inhibition of human wild type RSK1 using RBER-CHKtide as substrate preincubated for 2 hrs followed by ATP addition and measured every 2 mins for 2.5 hrs by spectrophotometric analysis	ic50	0.1400	uM
4-[1-ethyl-7-[(piperidin-4-ylamino)methyl]imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	1933327: Inhibition of RSK1 (unknown origin)	ic50	0.1550	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	624900: Binding constant for RSK1(Kin.Dom.1-N-terminal) kinase domain	kd	0.1600	uM
4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]phenol	435829: Binding constant for RPS6KA1(Kin.Dom.2 - C-terminal) kinase domain	kd	0.1700	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	435690: Binding constant for RPS6KA1(Kin.Dom.1 - N-terminal) kinase domain	kd	0.1800	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624900: Binding constant for RSK1(Kin.Dom.1-N-terminal) kinase domain	kd	0.1800	uM
3-[3-[4-(1-methylindol-3-yl)-2,5-dioxopyrrol-3-yl]indol-1-yl]propyl carbamimidothioate	2008182: Inhibition of RSK1 (unknown origin)	ic50	0.2000	uM
6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	527871: Inhibition of RSK1 by Hot Spot filtration binding assay	ic50	0.2100	uM
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol	624901: Binding constant for RSK1(Kin.Dom.2-C-terminal) kinase domain	kd	0.2200	uM
4-[2-[4-[3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenoxy]ethyl]morpholine	527871: Inhibition of RSK1 by Hot Spot filtration binding assay	ic50	0.2200	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425159: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.2510	uM
4-[7-(3-aminopropoxy)-4-(2-cyclopropylethynyl)-1-ethylimidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine	1798494: In Vitro Kinase Inhibition Assay from Article 10.1021/jm8004527: “Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.”	ic50	0.2510	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, affects expression	5
Acetaminophen	affects expression, increases expression	3
Nickel	decreases expression, increases expression	3
Ozone	increases abundance, affects expression, affects cotreatment, increases oxidation	3
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
U 0126	decreases reaction, increases phosphorylation	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression	2
Calcitriol	increases expression, affects cotreatment	2
Cisplatin	affects cotreatment, increases expression, increases phosphorylation, decreases reaction	2
Quercetin	decreases activity, increases expression	2
Tobacco Smoke Pollution	increases expression, increases methylation	2
Tretinoin	increases phosphorylation, increases reaction, increases expression	2
Cyclosporine	decreases expression	2
FR900359	affects phosphorylation	1
ZCL-082	decreases reaction, increases phosphorylation, increases stability	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, affects localization	1
beta-lapachone	increases expression	1
sodium bichromate	decreases expression	1
butyraldehyde	increases expression	1
avermectin	decreases phosphorylation	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
ochratoxin A	increases phosphorylation	1
enzacamene	increases phosphorylation	1
fasudil	decreases activity	1
protopanaxadiol	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1

ChEMBL screening assays

785 unique, capped per target: 784 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003311	Binding	Inhibition of RSK1 at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem
CHEMBL4424897	ADMET	Inhibition of human full-length N-terminal His-tagged p70S6K expressed in baculovirus infected Sf21 insect cells using CKRRRLASLR as substrate	Optimization of an azetidine series as inhibitors of colony stimulating factor-1 receptor (CSF-1R) Type II to lead to the clinical candidate JTE-952. — Bioorg Med Chem Lett

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 2 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5X4	SEES3-1V human RPS6KA1, clone1	Embryonic stem cell	Male
CVCL_A5X5	SEES3-1V human RPS6KA1, clone2	Embryonic stem cell	Male
CVCL_B8NY	Abcam HCT 116 RPS6KA1 KO	Cancer cell line	Male
CVCL_B9RA	Abcam A-549 RPS6KA1 KO	Cancer cell line	Male
CVCL_D2H6	Abcam MCF-7 RPS6KA1 KO	Cancer cell line	Female
CVCL_D8UR	Ubigene HCT 116 RPS6KA1 KO	Cancer cell line	Male
CVCL_E0MZ	Ubigene HeLa RPS6KA1 KO	Cancer cell line	Female
CVCL_TJ60	HAP1 RPS6KA1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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