Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTITX14U)

• DOT Name: Class E basic helix-loop-helix protein 40 (BHLHE40)
• Synonyms: bHLHe40; Class B basic helix-loop-helix protein 2; bHLHb2; Differentially expressed in chondrocytes protein 1; DEC1; Enhancer-of-split and hairy-related protein 2; SHARP-2; Stimulated by retinoic acid gene 13 protein
• Gene Name: BHLHE40
• Related Disease:
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Autoimmune disease
  Bipolar depression
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Clear cell renal carcinoma
  Colon carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Esophageal cancer
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Head-neck squamous cell carcinoma
  Hypothyroidism
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Myocardial ischemia
  Neoplasm
  Neoplasm of esophagus
  Nervous system inflammation
  Non-small-cell lung cancer
  Obesity
  Schizophrenia
  Sleep-wake disorder
  Squamous cell carcinoma
  Stomach cancer
  Triple negative breast cancer
  Carcinoma
  Prostate cancer
  Prostate carcinoma
  Esophageal squamous cell carcinoma
  Melanoma
  Myocardial infarction
  Osteoporosis
  Pancreatic cancer
  Prostate neoplasm
• UniProt ID: BHE40_HUMAN
• Pfam ID: PF07527 ; PF00010
• Sequence:
  MERIPSAQPPPACLPKAPGLEHGDLPGMYPAHMYQVYKSRRGIKRSEDSKETYKLPHRLI
  EKKRRDRINECIAQLKDLLPEHLKLTTLGHLEKAVVLELTLKHVKALTNLIDQQQQKIIA
  LQSGLQAGELSGRNVETGQEMFCSGFQTCAREVLQYLAKHENTRDLKSSQLVTHLHRVVS
  ELLQGGTSRKPSDPAPKVMDFKEKPSSPAKGSEGPGKNCVPVIQRTFAHSSGEQSGSDTD
  TDSGYGGESEKGDLRSEQPCFKSDHGRRFTMGERIGAIKQESEEPPTKKNRMQLSDDEGH
  FTSSDLISSPFLGPHPHQPPFCLPFYLIPPSATAYLPMLEKCWYPTSVPVLYPGLNASAA
  ALSSFMNPDKISAPLLMPQRLPSPLPAHPSVDSSVLLQALKPIPPLNLETKD
• Function: Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes. Acts as the negative limb of a novel autoregulatory feedback loop (DEC loop) which differs from the one formed by the PER and CRY transcriptional repressors (PER/CRY loop). Both these loops are interlocked as it represses the expression of PER1/2 and in turn is repressed by PER1/2 and CRY1/2. Represses the activity of the circadian transcriptional activator: CLOCK-BMAL1|BMAL2 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes. Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2. Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA and NR1H3/LXRA transactivation activity. May be involved in the regulation of chondrocyte differentiation via the cAMP pathway. Represses the transcription of NR0B2 and attentuates the transactivation of NR0B2 by the CLOCK-BMAL1 complex. Drives the circadian rhythm of blood pressure through transcriptional repression of ATP1B1 in the cardiovascular system.
• Tissue Specificity: Expressed in cartilage, spleen, intestine, lung, and to a lesser extent in heart, brain, liver, muscle and stomach.
• KEGG Pathway: Circadian rhythm (hsa04710)
• Reactome Pathway: BMAL1 (R-HSA-1368108)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[6]
Bipolar depression	DISA75FU	Strong	Biomarker	[7]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[9]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[11]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[12]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[12]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[13]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[14]
Glioma	DIS5RPEH	Strong	Biomarker	[15]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[16]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[17]
Lung cancer	DISCM4YA	Strong	Altered Expression	[18]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[18]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[19]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[20]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[9]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[18]
Obesity	DIS47Y1K	Strong	Biomarker	[22]
Schizophrenia	DISSRV2N	Strong	Biomarker	[23]
Sleep-wake disorder	DISOBM0Q	Strong	Biomarker	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[24]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[13]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[25]
Carcinoma	DISH9F1N	moderate	Biomarker	[26]
Prostate cancer	DISF190Y	moderate	Biomarker	[27]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[27]
Esophageal squamous cell carcinoma	DIS5N2GV	Limited	Altered Expression	[28]
Melanoma	DIS1RRCY	Limited	Biomarker	[29]
Myocardial infarction	DIS655KI	Limited	Altered Expression	[30]
Osteoporosis	DISF2JE0	Limited	Altered Expression	[31]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[32]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[33]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Class E basic helix-loop-helix protein 40 (BHLHE40) decreases the response to substance of Arsenic.	[81]

2 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 Class E basic helix-loop-helix protein 40 (BHLHE40).	[34]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Class E basic helix-loop-helix protein 40 (BHLHE40).	[68]

49 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 Class E basic helix-loop-helix protein 40 (BHLHE40).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[39]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[40]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[41]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[42]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[43]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[44]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[45]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[46]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[47]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[48]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[49]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[50]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[51]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[52]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[53]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[54]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[55]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[56]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[56]
Methoxsalen	DME8FZ9	Approved	Methoxsalen decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[57]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[58]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[59]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[60]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[61]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[40]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[62]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[63]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[64]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[65]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[66]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[67]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[69]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[70]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[71]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[72]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[73]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[74]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[75]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[76]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[77]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[78]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[41]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[79]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Class E basic helix-loop-helix protein 40 (BHLHE40).	[80]

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