Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAVZJ3J)

• DOT Name: Ribosomal protein S6 kinase alpha-5 (RPS6KA5)
• Synonyms: S6K-alpha-5; EC 2.7.11.1; 90 kDa ribosomal protein S6 kinase 5; Nuclear mitogen- and stress-activated protein kinase 1; RSK-like protein kinase; RSKL
• Gene Name: RPS6KA5
• UniProt ID: KS6A5_HUMAN
• PDB ID: 1VZO; 3KN5; 3KN6; 7UP4; 7UP5; 7UP6; 7UP7; 7UP8
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF00433
• Sequence:
  MEEEGGSSGGAAGTSADGGDGGEQLLTVKHELRTANLTGHAEKVGIENFELLKVLGTGAY
  GKVFLVRKISGHDTGKLYAMKVLKKATIVQKAKTTEHTRTERQVLEHIRQSPFLVTLHYA
  FQTETKLHLILDYINGGELFTHLSQRERFTEHEVQIYVGEIVLALEHLHKLGIIYRDIKL
  ENILLDSNGHVVLTDFGLSKEFVADETERAYSFCGTIEYMAPDIVRGGDSGHDKAVDWWS
  LGVLMYELLTGASPFTVDGEKNSQAEISRRILKSEPPYPQEMSALAKDLIQRLLMKDPKK
  RLGCGPRDADEIKEHLFFQKINWDDLAAKKVPAPFKPVIRDELDVSNFAEEFTEMDPTYS
  PAALPQSSEKLFQGYSFVAPSILFKRNAAVIDPLQFHMGVERPGVTNVARSAMMKDSPFY
  QHYDLDLKDKPLGEGSFSICRKCVHKKSNQAFAVKIISKRMEANTQKEITALKLCEGHPN
  IVKLHEVFHDQLHTFLVMELLNGGELFERIKKKKHFSETEASYIMRKLVSAVSHMHDVGV
  VHRDLKPENLLFTDENDNLEIKIIDFGFARLKPPDNQPLKTPCFTLHYAAPELLNQNGYD
  ESCDLWSLGVILYTMLSGQVPFQSHDRSLTCTSAVEIMKKIKKGDFSFEGEAWKNVSQEA
  KDLIQGLLTVDPNKRLKMSGLRYNEWLQDGSQLSSNPLMTPDILGSSGAAVHTCVKATFH
  AFNKYKREGFCLQNVDKAPLAKRRKMKKTSTSTETRSSSSESSHSSSSHSHGKTTPTKTL
  QPSNPADSNNPETLFQFSDSVA
• Function: Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factors RELA, STAT3 and ETV1/ER81, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression. In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress. In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential. Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation. Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors. Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury. Phosphorylates TRIM7 at 'Ser-107' in response to growth factor signaling via the MEK/ERK pathway, thereby stimulating its ubiquitin ligase activity.
• Tissue Specificity: Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  TNF sig.ling pathway (hsa04668)
  Circadian entrainment (hsa04713)
  Neurotrophin sig.ling pathway (hsa04722)
  Shigellosis (hsa05131)
  Pathways in cancer (hsa05200)
  MicroR.s in cancer (hsa05206)
  Bladder cancer (hsa05219)
• Reactome Pathway:
  CREB phosphorylation (R-HSA-199920)
  NCAM signaling for neurite out-growth (R-HSA-375165)
  Recycling pathway of L1 (R-HSA-437239)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  ERK/MAPK targets (R-HSA-198753)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[1]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[11]
Ximelegatran	DMU8ANS	Approved	Ximelegatran decreases the activity of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[19]
Z-Pro-Prolinal	DM43O2U	Investigative	Z-Pro-Prolinal decreases the expression of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[20]
H-89	DM4RVGO	Investigative	H-89 decreases the activity of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[12]
Fasudil	DMTCNOM	Investigative	Fasudil decreases the activity of Ribosomal protein S6 kinase alpha-5 (RPS6KA5).	[12]

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-5 (RPS6KA5).	[14]

References

• [1] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Quercetin augments TRAIL-induced apoptotic death: involvement of the ERK signal transduction pathway. Biochem Pharmacol. 2008 May 15;75(10):1946-58. doi: 10.1016/j.bcp.2008.02.016. Epub 2008 Mar 10.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] 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.
• [17] 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.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Prolyl endopeptidase is involved in cellular signalling in human neuroblastoma SH-SY5Y cells. Neurosignals. 2011;19(2):97-109. doi: 10.1159/000326342. Epub 2011 Apr 10.