Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDOTWU4)

• DOT Name: Ribosomal protein S6 kinase alpha-1 (RPS6KA1)
• Synonyms: S6K-alpha-1; EC 2.7.11.1; 90 kDa ribosomal protein S6 kinase 1; p90-RSK 1; p90RSK1; p90S6K; MAP kinase-activated protein kinase 1a; MAPK-activated protein kinase 1a; MAPKAP kinase 1a; MAPKAPK-1a; Ribosomal S6 kinase 1; RSK-1
• Gene Name: RPS6KA1
• UniProt ID: KS6A1_HUMAN
• PDB ID: 2WNT; 2Z7Q; 2Z7R; 2Z7S; 3RNY; 3TEI; 4H3P; 4NIF; 5CSF; 5CSI; 5CSJ; 5CSN; 5N7D; 5N7F; 5N7G; 5V61; 5V62; 6TWY; 7P74; 7PC8; 7QQL; 8WF4
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF00433
• Sequence:
  MPLAQLKEPWPLMELVPLDPENGQTSGEEAGLQPSKDEGVLKEISITHHVKAGSEKADPS
  HFELLKVLGQGSFGKVFLVRKVTRPDSGHLYAMKVLKKATLKVRDRVRTKMERDILADVN
  HPFVVKLHYAFQTEGKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALGLDHLHS
  LGIIYRDLKPENILLDEEGHIKLTDFGLSKEAIDHEKKAYSFCGTVEYMAPEVVNRQGHS
  HSADWWSYGVLMFEMLTGSLPFQGKDRKETMTLILKAKLGMPQFLSTEAQSLLRALFKRN
  PANRLGSGPDGAEEIKRHVFYSTIDWNKLYRREIKPPFKPAVAQPDDTFYFDTEFTSRTP
  KDSPGIPPSAGAHQLFRGFSFVATGLMEDDGKPRAPQAPLHSVVQQLHGKNLVFSDGYVV
  KETIGVGSYSECKRCVHKATNMEYAVKVIDKSKRDPSEEIEILLRYGQHPNIITLKDVYD
  DGKHVYLVTELMRGGELLDKILRQKFFSEREASFVLHTIGKTVEYLHSQGVVHRDLKPSN
  ILYVDESGNPECLRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDEGCDIWSL
  GILLYTMLAGYTPFANGPSDTPEEILTRIGSGKFTLSGGNWNTVSETAKDLVSKMLHVDP
  HQRLTAKQVLQHPWVTQKDKLPQSQLSHQDLQLVKGAMAATYSALNSSKPTPQLKPIESS
  ILAQRRVRKLPSTTL
• 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.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Oocyte meiosis (hsa04114)
  mTOR sig.ling pathway (hsa04150)
  Thermogenesis (hsa04714)
  Long-term potentiation (hsa04720)
  Neurotrophin sig.ling pathway (hsa04722)
  Progesterone-mediated oocyte maturation (hsa04914)
  Insulin resistance (hsa04931)
  Yersinia infection (hsa05135)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  CREB phosphorylation (R-HSA-199920)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Recycling pathway of L1 (R-HSA-437239)
  CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling (R-HSA-442742)
  RSK activation (R-HSA-444257)
  Gastrin-CREB signalling pathway via PKC and MAPK (R-HSA-881907)
  ERK/MAPK targets (R-HSA-198753)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Ribosomal protein S6 kinase alpha-1 (RPS6KA1) affects the response to substance of Ethanol.	[22]
Insulin	DMB7CE0	Approved	Ribosomal protein S6 kinase alpha-1 (RPS6KA1) increases the Chromosomal abnormalities and abnormal gene carriers ADR of Insulin.	[23]

20 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[9]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the activity of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[17]
Purvalanol A	DMNQ7TM	Investigative	Purvalanol A decreases the activity of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[20]
Fasudil	DMTCNOM	Investigative	Fasudil decreases the activity of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[21]
SU 6656	DMF1P6W	Investigative	SU 6656 decreases the activity of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[20]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the phosphorylation of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the phosphorylation of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[18]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the phosphorylation of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[19]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Ribosomal protein S6 kinase alpha-1 (RPS6KA1).	[14]

References

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• [19] Rapamycin induces transactivation of the EGFR and increases cell survival. Oncogene. 2009 Mar 5;28(9):1187-96. doi: 10.1038/onc.2008.490. Epub 2009 Jan 19.
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• [23] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.