Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNQ3QUC)

• DOT Name: HMG box transcription factor BBX (BBX)
• Synonyms: Bobby sox homolog; HMG box-containing protein 2
• Gene Name: BBX
• Related Disease:
  Major depressive disorder
  Mood disorder
  Myelodysplastic syndrome
  Schizophrenia
  Age-related macular degeneration
  Alopecia
• UniProt ID: BBX_HUMAN
• Pfam ID: PF09667 ; PF00505
• Sequence:
  MKGSNRNKDHSAEGEGVGKRPKRKCLQWHPLLAKKLLDFSEEEEEEDEEEDIDKVQLLGA
  DGLEQDVGETEDDESPEQRARRPMNAFLLFCKRHRSLVRQEHPRLDNRGATKILADWWAV
  LDPKEKQKYTDMAKEYKDAFMKANPGYKWCPTTNKPVKSPTPTVNPRKKLWAFPSDSSRD
  LPSPKKAKTEEMPQLNFGMADPTQMGGLSMLLLAGEHALGTPEVSSGTCRPDVSESPELR
  QKSPLFQFAEISSSTSHSDASTKQCQTSALFQFAEISSNTSQLGGAEPVKRCGKSALFQL
  AEMCLASEGMKMEESKLIKAKESDGGRIKELEKGKEEKEIKMEKTDETRLQKEAEFEKSA
  KENLRDSKELRNFEALQIDDIMAIKMEDPKEIRKEELEEDHKCSHFPDFSYSASSKIIIS
  DVPSRKDHMCHPHGIMIIEDPAALNKPEKLKKKKKKSKMDRHGNDKSTPKKTCKKRQSSE
  SDIESVIYTIEAVAKGDWGIEKLGDTPRKKVRTSSSGKGSILDAKPPKKKVKSREKKMSK
  EKSSDTTKESRPPDFISISASKNISGETPEGIKAEPLTPMEDALPPSLSGQAKPEDSDCH
  RKIETCGSRKSERSCKGALYKTLVSEGMLTSLRANVDRGKRSSGKGNSSDHEGCWNEESW
  TFSQSGTSGSKKFKKTKPKEDCLLGSAKLDEEFEKKFNSLPQYSPVTFDRKCVPVPRKKK
  KTGNVSSEPTKTSKGPFQSQKKNLFHKIVSKYKHKKEKPNVPEKGSGDKWSNKQLFLDAI
  HPTEAIFSEDRNTMEPVHKVKNIPSIFNTPEPTTTQEPLVGSQKRKARKTKITHLVRTAD
  GRVSPAGGTLDDKPKEQLQRSLPKATETDCNDKCSHNTEVGETRSSTPEMPAVSAFFSLA
  ALAEVAAMENVHRGQRSTPLTHDGQPKEMPQAPVLISCADQ
• Function: Transcription factor that is necessary for cell cycle progression from G1 to S phase.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[1]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[4]
Alopecia	DIS37HU4	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	HMG box transcription factor BBX (BBX) affects the response to substance of Fluorouracil.	[22]
Mitoxantrone	DMM39BF	Approved	HMG box transcription factor BBX (BBX) affects the response to substance of Mitoxantrone.	[22]

15 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 HMG box transcription factor BBX (BBX).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of HMG box transcription factor BBX (BBX).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of HMG box transcription factor BBX (BBX).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of HMG box transcription factor BBX (BBX).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of HMG box transcription factor BBX (BBX).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of HMG box transcription factor BBX (BBX).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of HMG box transcription factor BBX (BBX).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of HMG box transcription factor BBX (BBX).	[13]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of HMG box transcription factor BBX (BBX).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of HMG box transcription factor BBX (BBX).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of HMG box transcription factor BBX (BBX).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of HMG box transcription factor BBX (BBX).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of HMG box transcription factor BBX (BBX).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of HMG box transcription factor BBX (BBX).	[20]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of HMG box transcription factor BBX (BBX).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of HMG box transcription factor BBX (BBX).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of HMG box transcription factor BBX (BBX).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of HMG box transcription factor BBX (BBX).	[19]

References

• [1] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [2] Durable long-term responses in patients with myelodysplastic syndromes treated with lenalidomide.Clin Lymphoma Myeloma. 2009 Jun;9(3):E10-3. doi: 10.3816/CLM.2009.n.053.
• [3] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [4] Association of coding and UTR variants in the known regions with wet age-related macular degeneration in Han Chinese population.J Hum Genet. 2018 Oct;63(10):1055-1070. doi: 10.1038/s10038-018-0490-3. Epub 2018 Jul 19.
• [5] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [11] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] 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.
• [14] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] 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.
• [21] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [22] 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.