Details of Drug Off-Target (DOT)

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

• DOT Name: Ribosomal protein S6 kinase alpha-2 (RPS6KA2)
• Synonyms: S6K-alpha-2; EC 2.7.11.1; 90 kDa ribosomal protein S6 kinase 2; p90-RSK 2; p90RSK2; MAP kinase-activated protein kinase 1c; MAPK-activated protein kinase 1c; MAPKAP kinase 1c; MAPKAPK-1c; Ribosomal S6 kinase 3; RSK-3; pp90RSK3
• Gene Name: RPS6KA2
• UniProt ID: KS6A2_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF00433
• Sequence:
  MDLSMKKFAVRRFFSVYLRRKSRSKSSSLSRLEEEGVVKEIDISHHVKEGFEKADPSQFE
  LLKVLGQGSYGKVFLVRKVKGSDAGQLYAMKVLKKATLKVRDRVRSKMERDILAEVNHPF
  IVKLHYAFQTEGKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALALDHLHSLGI
  IYRDLKPENILLDEEGHIKITDFGLSKEAIDHDKRAYSFCGTIEYMAPEVVNRRGHTQSA
  DWWSFGVLMFEMLTGSLPFQGKDRKETMALILKAKLGMPQFLSGEAQSLLRALFKRNPCN
  RLGAGIDGVEEIKRHPFFVTIDWNTLYRKEIKPPFKPAVGRPEDTFHFDPEFTARTPTDS
  PGVPPSANAHHLFRGFSFVASSLIQEPSQQDLHKVPVHPIVQQLHGNNIHFTDGYEIKED
  IGVGSYSVCKRCVHKATDTEYAVKIIDKSKRDPSEEIEILLRYGQHPNIITLKDVYDDGK
  FVYLVMELMRGGELLDRILRQRYFSEREASDVLCTITKTMDYLHSQGVVHRDLKPSNILY
  RDESGSPESIRVCDFGFAKQLRAGNGLLMTPCYTANFVAPEVLKRQGYDAACDIWSLGIL
  LYTMLAGFTPFANGPDDTPEEILARIGSGKYALSGGNWDSISDAAKDVVSKMLHVDPHQR
  LTAMQVLKHPWVVNREYLSPNQLSRQDVHLVKGAMAATYFALNRTPQAPRLEPVLSSNLA
  QRRGMKRLTSTRL
• Function: Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of transcription factors, regulates translation, and mediates cellular proliferation, survival, and differentiation. May function as tumor suppressor in epithelial ovarian cancer cells.
• Tissue Specificity: Widely expressed with higher expression in lung, skeletal muscle, brain, uterus, ovary, thyroid and prostate.
• 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 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cyclophosphamide	DM4O2Z7	Approved	Ribosomal protein S6 kinase alpha-2 (RPS6KA2) affects the response to substance of Cyclophosphamide.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[9]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[11]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[12]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[13]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[14]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[21]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[22]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[10]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the phosphorylation of Ribosomal protein S6 kinase alpha-2 (RPS6KA2).	[15]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact. 2010 Oct 6;188(1):214-9.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [12] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [13] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [14] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [15] Glycogen synthase kinase 3 regulates cell death and survival signaling in tumor cells under redox stress. Neoplasia. 2014 Sep;16(9):710-22.
• [16] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [17] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [18] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [22] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [23] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.