Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTIXKA4)

• DTT Name: Ribosomal protein S6 kinase alpha-1 (RSK1)
• Synonyms: p90S6K; p90RSK1; p90-RSK 1; S6K-alpha-1; Ribosomal S6 kinase 1; RSK-1; MAPKAPK1A; MAPKAPK-1a; MAPKAP kinase 1a; MAPK-activated protein kinase 1a; MAP kinase-activated protein kinase 1a; 90 kDa ribosomal protein S6 kinase 1
• Gene Name: RPS6KA1
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Kinase
• UniProt ID: KS6A1_HUMAN
• TTD ID: T83202
• EC Number: EC 2.7.11.1
• Sequence:
  MPLAQLKEPWPLMELVPLDPENGQTSGEEAGLQPSKDEGVLKEISITHHVKAGSEKADPS
  HFELLKVLGQGSFGKVFLVRKVTRPDSGHLYAMKVLKKATLKVRDRVRTKMERDILADVN
  HPFVVKLHYAFQTEGKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALGLDHLHS
  LGIIYRDLKPENILLDEEGHIKLTDFGLSKEAIDHEKKAYSFCGTVEYMAPEVVNRQGHS
  HSADWWSYGVLMFEMLTGSLPFQGKDRKETMTLILKAKLGMPQFLSTEAQSLLRALFKRN
  PANRLGSGPDGAEEIKRHVFYSTIDWNKLYRREIKPPFKPAVAQPDDTFYFDTEFTSRTP
  KDSPGIPPSAGAHQLFRGFSFVATGLMEDDGKPRAPQAPLHSVVQQLHGKNLVFSDGYVV
  KETIGVGSYSECKRCVHKATNMEYAVKVIDKSKRDPSEEIEILLRYGQHPNIITLKDVYD
  DGKHVYLVTELMRGGELLDKILRQKFFSEREASFVLHTIGKTVEYLHSQGVVHRDLKPSN
  ILYVDESGNPECLRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDEGCDIWSL
  GILLYTMLAGYTPFANGPSDTPEEILTRIGSGKFTLSGGNWNTVSETAKDLVSKMLHVDP
  HQRLTAKQVLQHPWVTQKDKLPQSQLSHQDLQLVKGAMAATYSALNSSKPTPQLKPIESS
  ILAQRRVRKLPSTTL
• Function: 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. 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. 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.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Oocyte meiosis (hsa04114)
  mTOR signaling pathway (hsa04150)
  Thermogenesis (hsa04714)
  Long-term potentiation (hsa04720)
  Neurotrophin signaling 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 DTT

5 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,6-diazanaphthalenes and pyrido[2,3-d] pyrimidine derivative 1	DMUQ9CF	N. A.	N. A.	Patented	[1]
1,6-diazanaphthalenes and pyrido[2,3-d] pyrimidine derivative 2	DMPZ0U8	N. A.	N. A.	Patented	[1]
Heterocyclic derivative 26	DM56T1P	N. A.	N. A.	Patented	[1]
Pyrrolo[2,3-d]pyrimidine derivative 1	DMYUEA6	N. A.	N. A.	Patented	[1]
Pyrrolo[2,3-d]pyrimidine derivative 2	DMJFYK1	N. A.	N. A.	Patented	[1]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BI-D1870	DMK3SAF	Chronic lymphocytic leukaemia	2A82.0	Preclinical	[2]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GSK-1838705A	DM4HLK3	Discovery agent	N.A.	Investigative	[3]
PMID19364658C33	DMSE1C3	Discovery agent	N.A.	Investigative	[4]

References

• [1] Ribosomal S6 kinase (RSK) modulators: a patent review.Expert Opin Ther Pat. 2016 Sep;26(9):1061-78.
• [2] BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. Biochem J. 2007 Jan 1;401(1):29-38.
• [3] GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol Cancer Ther. 2009 Oct;8(10):2811-20.
• [4] Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem. 2009 May 1;17(9):3342-51.