Details of Drug Off-Target (DOT)

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

• DOT Name: Proto-oncogene c-Rel (REL)
• Gene Name: REL
• Related Disease: Immunodeficiency 92
• UniProt ID: REL_HUMAN
• Pfam ID: PF16179 ; PF00554
• Sequence:
  MASGAYNPYIEIIEQPRQRGMRFRYKCEGRSAGSIPGEHSTDNNRTYPSIQIMNYYGKGK
  VRITLVTKNDPYKPHPHDLVGKDCRDGYYEAEFGQERRPLFFQNLGIRCVKKKEVKEAII
  TRIKAGINPFNVPEKQLNDIEDCDLNVVRLCFQVFLPDEHGNLTTALPPVVSNPIYDNRA
  PNTAELRICRVNKNCGSVRGGDEIFLLCDKVQKDDIEVRFVLNDWEAKGIFSQADVHRQV
  AIVFKTPPYCKAITEPVTVKMQLRRPSDQEVSESMDFRYLPDEKDTYGNKAKKQKTTLLF
  QKLCQDHVETGFRHVDQDGLELLTSGDPPTLASQSAGITVNFPERPRPGLLGSIGEGRYF
  KKEPNLFSHDAVVREMPTGVSSQAESYYPSPGPISSGLSHHASMAPLPSSSWSSVAHPTP
  RSGNTNPLSSFSTRTLPSNSQGIPPFLRIPVGNDLNASNACIYNNADDIVGMEASSMPSA
  DLYGISDPNMLSNCSVNMMTTSSDSMGETDNPRLLSMNLENPSCNSVLDPRDLRQLHQMS
  SSSMSAGANSNTTVFVSQSDAFEGSDFSCADNSMINESGPSNSTNPNSHGFVQDSQYSGI
  GSMQNEQLSDSFPYEFFQV
• Function: Proto-oncogene that may play a role in differentiation and lymphopoiesis. NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The NF-kappa-B heterodimer RELA/p65-c-Rel is a transcriptional activator.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Transcriptio.l misregulation in cancer (hsa05202)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway: Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 92	DISR08MK	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Proto-oncogene c-Rel (REL).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Proto-oncogene c-Rel (REL).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proto-oncogene c-Rel (REL).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Proto-oncogene c-Rel (REL).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Proto-oncogene c-Rel (REL).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Proto-oncogene c-Rel (REL).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Proto-oncogene c-Rel (REL).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Proto-oncogene c-Rel (REL).	[9]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Proto-oncogene c-Rel (REL).	[10]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Proto-oncogene c-Rel (REL).	[11]
Ritonavir	DMU764S	Approved	Ritonavir decreases the activity of Proto-oncogene c-Rel (REL).	[12]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Proto-oncogene c-Rel (REL).	[8]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Proto-oncogene c-Rel (REL).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Proto-oncogene c-Rel (REL).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Proto-oncogene c-Rel (REL).	[11]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Proto-oncogene c-Rel (REL).	[18]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Proto-oncogene c-Rel (REL).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Norepinephrine	DMOUC09	Approved	Norepinephrine affects the localization of Proto-oncogene c-Rel (REL).	[13]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate affects the localization of Proto-oncogene c-Rel (REL).	[14]
PIPERINE	DMYEAB1	Phase 1/2	PIPERINE decreases the localization of Proto-oncogene c-Rel (REL).	[15]

References

• [1] Combined immunodeficiency in a patient with c-Rel deficiency. J Allergy Clin Immunol. 2019 Aug;144(2):606-608.e4. doi: 10.1016/j.jaci.2019.05.003. Epub 2019 May 16.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [4] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [5] 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.
• [6] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [7] Arsenic trioxide down-regulates antiapoptotic genes and induces cell death in mycosis fungoides tumors in a mouse model. Ann Oncol. 2008 Aug;19(8):1488-1494. doi: 10.1093/annonc/mdn056. Epub 2008 Mar 17.
• [8] Neuroprotective effects of glucomoringin-isothiocyanate against H(2)O(2)-Induced cytotoxicity in neuroblastoma (SH-SY5Y) cells. Neurotoxicology. 2019 Dec;75:89-104. doi: 10.1016/j.neuro.2019.09.008. Epub 2019 Sep 12.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [11] Sulforaphane increases drug-mediated cytotoxicity toward cancer stem-like cells of pancreas and prostate. Mol Ther. 2011 Jan;19(1):188-95.
• [12] Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir. Blood. 2006 Jan 15;107(2):716-24. doi: 10.1182/blood-2005-02-0735. Epub 2005 Sep 20.
• [13] Targeting activation of specific NF-B subunits prevents stress-dependent atherothrombotic gene expression. Mol Med. 2012 Dec 20;18(1):1375-86. doi: 10.2119/molmed.2012.00282.
• [14] Scoparone inhibits PMA-induced IL-8 and MCP-1 production through suppression of NF-kappaB activation in U937 cells. Life Sci. 2006 May 15;78(25):2937-43. doi: 10.1016/j.lfs.2005.11.020. Epub 2005 Dec 22.
• [15] Piperine is a potent inhibitor of nuclear factor-kappaB (NF-kappaB), c-Fos, CREB, ATF-2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells. Int Immunopharmacol. 2004 Dec 20;4(14):1795-803. doi: 10.1016/j.intimp.2004.08.005.
• [16] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [17] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [18] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [19] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.