Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRA4K2V)

• DOT Name: Delta-like protein 4 (DLL4)
• Synonyms: Drosophila Delta homolog 4; Delta4
• Gene Name: DLL4
• Related Disease:
  Adams-Oliver syndrome 6
  Adams-Oliver syndrome
  Aplasia cutis congenita
• UniProt ID: DLL4_HUMAN
• PDB ID: 5MVX
• Pfam ID: PF21700 ; PF01414 ; PF00008 ; PF07657
• Sequence:
  MAAASRSASGWALLLLVALWQQRAAGSGVFQLQLQEFINERGVLASGRPCEPGCRTFFRV
  CLKHFQAVVSPGPCTFGTVSTPVLGTNSFAVRDDSSGGGRNPLQLPFNFTWPGTFSLIIE
  AWHAPGDDLRPEALPPDALISKIAIQGSLAVGQNWLLDEQTSTLTRLRYSYRVICSDNYY
  GDNCSRLCKKRNDHFGHYVCQPDGNLSCLPGWTGEYCQQPICLSGCHEQNGYCSKPAECL
  CRPGWQGRLCNECIPHNGCRHGTCSTPWQCTCDEGWGGLFCDQDLNYCTHHSPCKNGATC
  SNSGQRSYTCTCRPGYTGVDCELELSECDSNPCRNGGSCKDQEDGYHCLCPPGYYGLHCE
  HSTLSCADSPCFNGGSCRERNQGANYACECPPNFTGSNCEKKVDRCTSNPCANGGQCLNR
  GPSRMCRCRPGFTGTYCELHVSDCARNPCAHGGTCHDLENGLMCTCPAGFSGRRCEVRTS
  IDACASSPCFNRATCYTDLSTDTFVCNCPYGFVGSRCEFPVGLPPSFPWVAVSLGVGLAV
  LLVLLGMVAVAVRQLRLRRPDDGSREAMNNLSDFQKDNLIPAAQLKNTNQKKELEVDCGL
  DKSNCGKQQNHTLDYNLAPGPLGRGTMPGKFPHSDKSLGEKAPLRLHSEKPECRISAICS
  PRDSMYQSVCLISEERNECVIATEV
• Function: Involved in the Notch signaling pathway as Notch ligand. Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types. During spinal cord neurogenesis, inhibits V2a interneuron fate.
• Tissue Specificity: Expressed in vascular endothelium.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Notch sig.ling pathway (hsa04330)
  Th1 and Th2 cell differentiation (hsa04658)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Breast cancer (hsa05224)
• Reactome Pathway:
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 t(7 (R-HSA-2660826)
  Constitutive Signaling by NOTCH1 HD Domain Mutants (R-HSA-2691232)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507)
  NOTCH4 Activation and Transmission of Signal to the Nucleus (R-HSA-9013700)
  M1580_K2555) Translocation Mutant (9)(NOTCH1)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adams-Oliver syndrome 6	DISGK6ZR	Definitive	Autosomal dominant	[1]
Adams-Oliver syndrome	DISQO525	Supportive	Autosomal dominant	[1]
Aplasia cutis congenita	DISMDAYM	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Delta-like protein 4 (DLL4).	[2]
Docetaxel	DMDI269	Approved	Docetaxel increases the expression of Delta-like protein 4 (DLL4).	[3]
Propranolol	DM79NTF	Approved	Propranolol decreases the expression of Delta-like protein 4 (DLL4).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Delta-like protein 4 (DLL4).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Delta-like protein 4 (DLL4).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Delta-like protein 4 (DLL4).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Delta-like protein 4 (DLL4).	[9]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Delta-like protein 4 (DLL4).	[10]

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 affects the methylation of Delta-like protein 4 (DLL4).	[6]

References

• [1] Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome. Am J Hum Genet. 2015 Sep 3;97(3):475-82. doi: 10.1016/j.ajhg.2015.07.015. Epub 2015 Aug 20.
• [2] Arsenic trioxide exerts anti-lung cancer activity by inhibiting angiogenesis. Curr Cancer Drug Targets. 2014;14(6):557-66. doi: 10.2174/1568009614666140725090000.
• [3] Role of delta-like ligand-4 in chemoresistance against docetaxel in MCF-7 cells. Hum Exp Toxicol. 2017 Apr;36(4):328-338. doi: 10.1177/0960327116650006. Epub 2016 Jun 22.
• [4] Propranolol inhibits proliferation and invasion of hemangioma-derived endothelial cells by suppressing the DLL4/Notch1/Akt pathway. Chem Biol Interact. 2018 Oct 1;294:28-33. doi: 10.1016/j.cbi.2018.08.018. Epub 2018 Aug 18.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [7] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.
• [10] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.