Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLU00JS)

• DOT Name: Proheparin-binding EGF-like growth factor (HBEGF)
• Gene Name: HBEGF
• UniProt ID: HBEGF_HUMAN
• PDB ID: 1XDT; 2M8S
• Sequence:
  MKLLPSVVLKLFLAAVLSALVTGESLERLRRGLAAGTSNPDPPTVSTDQLLPLGGGRDRK
  VRDLQEADLDLLRVTLSSKPQALATPNKEEHGKRKKKGKGLGKKRDPCLRKYKDFCIHGE
  CKYVKELRAPSCICHPGYHGERCHGLSLPVENRLYTYDHTTILAVVAVVLSSVCLLVIVG
  LLMFRYHRRGGYDVENEEKVKLGMTNSH
• Function: Growth factor that mediates its effects via EGFR, ERBB2 and ERBB4. Required for normal cardiac valve formation and normal heart function. Promotes smooth muscle cell proliferation. May be involved in macrophage-mediated cellular proliferation. It is mitogenic for fibroblasts, but not endothelial cells. It is able to bind EGF receptor/EGFR with higher affinity than EGF itself and is a far more potent mitogen for smooth muscle cells than EGF. Also acts as a diphtheria toxin receptor.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  ErbB sig.ling pathway (hsa04012)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Coro.virus disease - COVID-19 (hsa05171)
  Proteoglycans in cancer (hsa05205)
  Bladder cancer (hsa05219)
• Reactome Pathway:
  Signaling by ERBB4 (R-HSA-1236394)
  SHC1 events in ERBB2 signaling (R-HSA-1250196)
  PI3K events in ERBB4 signaling (R-HSA-1250342)
  SHC1 events in ERBB4 signaling (R-HSA-1250347)
  Nuclear signaling by ERBB4 (R-HSA-1251985)
  PIP3 activates AKT signaling (R-HSA-1257604)
  Signaling by EGFR (R-HSA-177929)
  GRB2 events in EGFR signaling (R-HSA-179812)
  GAB1 signalosome (R-HSA-180292)
  SHC1 events in EGFR signaling (R-HSA-180336)
  EGFR downregulation (R-HSA-182971)
  GRB2 events in ERBB2 signaling (R-HSA-1963640)
  PI3K events in ERBB2 signaling (R-HSA-1963642)
  EGFR interacts with phospholipase C-gamma (R-HSA-212718)
  EGFR Transactivation by Gastrin (R-HSA-2179392)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Uptake and function of diphtheria toxin (R-HSA-5336415)
  Inhibition of Signaling by Overexpressed EGFR (R-HSA-5638303)
  RAF/MAP kinase cascade (R-HSA-5673001)
  ERBB2 Regulates Cell Motility (R-HSA-6785631)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  ERBB2 Activates PTK6 Signaling (R-HSA-8847993)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  PTK6 promotes HIF1A stabilization (R-HSA-8857538)
  Downregulation of ERBB2 signaling (R-HSA-8863795)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  Estrogen-dependent nuclear events downstream of ESR-membrane signaling (R-HSA-9634638)
  Signaling by ERBB2 KD Mutants (R-HSA-9664565)
  Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686)
  Signaling by ERBB2 (R-HSA-1227986)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Crizotinib	DM4F29C	Approved	Proheparin-binding EGF-like growth factor (HBEGF) decreases the response to substance of Crizotinib.	[41]
NVP-TAE684	DMFZXI2	Investigative	Proheparin-binding EGF-like growth factor (HBEGF) decreases the response to substance of NVP-TAE684.	[41]

46 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 Proheparin-binding EGF-like growth factor (HBEGF).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[15]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[3]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[17]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[18]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[19]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[13]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[20]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[21]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[3]
Dactinomycin	DM2YGNW	Approved	Dactinomycin decreases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[22]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[23]
Bleomycin	DMNER5S	Approved	Bleomycin increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[24]
Sodium chloride	DMM3950	Approved	Sodium chloride increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[25]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[27]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[28]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[31]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[36]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[37]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[38]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[39]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[18]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[3]
All-trans-retinal	DM6CEVB	Investigative	All-trans-retinal increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[40]
Tyrphostin Ag-1478	DM87ZIH	Investigative	Tyrphostin Ag-1478 increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[22]
Sucrose	DMVWUCF	Investigative	Sucrose increases the expression of Proheparin-binding EGF-like growth factor (HBEGF).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chondroitin sulfate	DM0N19Y	Phase 4	Chondroitin sulfate affects the binding of Proheparin-binding EGF-like growth factor (HBEGF).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Proheparin-binding EGF-like growth factor (HBEGF).	[29]

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