Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZTK2TV)

• DOT Name: Isthmin-1 (ISM1)
• Gene Name: ISM1
• Related Disease:
  Hepatocellular carcinoma
  Gastric cancer
  Neoplasm
  Schizophrenia
  Stomach cancer
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Mast cell leukaemia
  Systemic mastocytosis
• UniProt ID: ISM1_HUMAN
• Pfam ID: PF03782 ; PF00090
• Sequence:
  MVRLAAELLLLLGLLLLTLHITVLRGSGAADGPDAAAGNASQAQLQNNLNVGSDTTSETS
  FSLSKEAPREHLDHQAAHQPFPRPRFRQETGHPSLQRDFPRSFLLDLPNFPDLSKADING
  QNPNIQVTIEVVDGPDSEADKDQHPENKPSWSVPSPDWRAWWQRSLSLARANSGDQDYKY
  DSTSDDSNFLNPPRGWDHTAPGHRTFETKDQPEYDSTDGEGDWSLWSVCSVTCGNGNQKR
  TRSCGYACTATESRTCDRPNCPGIEDTFRTAATEVSLLAGSEEFNATKLFEVDTDSCERW
  MSCKSEFLKKYMHKVMNDLPSCPCSYPTEVAYSTADIFDRIKRKDFRWKDASGPKEKLEI
  YKPTARYCIRSMLSLESTTLAAQHCCYGDNMQLITRGKGAGTPNLISTEFSAELHYKVDV
  LPWIICKGDWSRYNEARPPNNGQKCTESPSDEDYIKQFQEAREY
• Function: Acts as an angiogenesis inhibitor.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Colon cancer	DISVC52G	moderate	Altered Expression	[6]
Colon carcinoma	DISJYKUO	moderate	Altered Expression	[6]
Mast cell leukaemia	DIS7VQW9	Limited	Biomarker	[7]
Systemic mastocytosis	DISNQ2OY	Limited	Biomarker	[7]

4 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 Isthmin-1 (ISM1).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Isthmin-1 (ISM1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Isthmin-1 (ISM1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Isthmin-1 (ISM1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Isthmin-1 (ISM1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Isthmin-1 (ISM1).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Isthmin-1 (ISM1).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Isthmin-1 (ISM1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Isthmin-1 (ISM1).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Isthmin-1 (ISM1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Isthmin-1 (ISM1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Isthmin-1 (ISM1).	[18]

References

• [1] hsa_circ_0091570 acts as a ceRNA to suppress hepatocellular cancer progression by sponging hsa-miR-1307.Cancer Lett. 2019 Sep 28;460:128-138. doi: 10.1016/j.canlet.2019.06.007. Epub 2019 Jun 14.
• [2] Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer.Oncotarget. 2014 Apr 30;5(8):2318-29. doi: 10.18632/oncotarget.1913.
• [3] Cognitive functioning in patients with low-grade glioma: effects of hemispheric tumor location and surgical procedure.J Neurosurg. 2019 Nov 15;133(6):1671-1682. doi: 10.3171/2019.8.JNS191667.
• [4] A phase II study to evaluate the pharmacokinetics, safety, and tolerability of Risperidone ISM multiple intramuscular injections once every 4 weeks in patients with schizophrenia.Int Clin Psychopharmacol. 2018 Mar;33(2):79-87. doi: 10.1097/YIC.0000000000000203.
• [5] Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction.Cell Death Differ. 2014 May;21(5):797-810. doi: 10.1038/cdd.2014.3. Epub 2014 Jan 24.
• [6] miR-1307-3p overexpression inhibits cell proliferation and promotes cell apoptosis by targeting ISM1 in colon cancer.Mol Cell Probes. 2019 Dec;48:101445. doi: 10.1016/j.mcp.2019.101445. Epub 2019 Sep 9.
• [7] Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management.Am J Hematol. 2019 Mar;94(3):363-377. doi: 10.1002/ajh.25371. Epub 2019 Jan 2.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] 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.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.