Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8CNKBO)

• DOT Name: Protein-S-isoprenylcysteine O-methyltransferase (ICMT)
• Synonyms: EC 2.1.1.100; Isoprenylcysteine carboxylmethyltransferase; Prenylated protein carboxyl methyltransferase; PPMT; Prenylcysteine carboxyl methyltransferase; pcCMT
• Gene Name: ICMT
• Related Disease:
  Lung cancer
  Lung carcinoma
  Acute myelogenous leukaemia
  Cervical cancer
  Cervical carcinoma
  Epithelial ovarian cancer
  Hutchinson-Gilford progeria syndrome
  Melanoma
  Ovarian cancer
  Ovarian neoplasm
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Bone osteosarcoma
  Nasopharyngeal carcinoma
  Neoplasm
  Osteosarcoma
  Patent ductus arteriosus
• UniProt ID: ICMT_HUMAN
• EC Number: 2.1.1.100
• Pfam ID: PF04140
• Sequence:
  MAGCAARAPPGSEARLSLATFLLGASVLALPLLTRAGLQGRTGLALYVAGLNALLLLLYR
  PPRYQIAIRACFLGFVFGCGTLLSFSQSSWSHFGWYMCSLSLFHYSEYLVTAVNNPKSLS
  LDSFLLNHSLEYTVAALSSWLEFTLENIFWPELKQITWLSVTGLLMVVFGECLRKAAMFT
  AGSNFNHVVQNEKSDTHTLVTSGVYAWFRHPSYVGWFYWSIGTQVMLCNPICGVSYALTV
  WRFFRDRTEEEEISLIHFFGEEYLEYKKRVPTGLPFIKGVKVDL
• Function: Catalyzes the post-translational methylation of isoprenylated C-terminal cysteine residues.
• Tissue Specificity: Ubiquitously expressed. Expressed at higher levels in the cerebellum and putamen than in other brain regions. Abundant expression seen in the Purkinje cells and pontine neurons.
• KEGG Pathway: Terpenoid backbone biosynthesis (hsa00900)
• Reactome Pathway:
  RAS processing (R-HSA-9648002)
  Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation (R-HSA-163841)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[4]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[4]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[7]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[8]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[9]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[3]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[9]
Patent ductus arteriosus	DIS9P8YS	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Protein-S-isoprenylcysteine O-methyltransferase (ICMT) affects the response to substance of Mitomycin.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein-S-isoprenylcysteine O-methyltransferase (ICMT).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein-S-isoprenylcysteine O-methyltransferase (ICMT).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Protein-S-isoprenylcysteine O-methyltransferase (ICMT).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein-S-isoprenylcysteine O-methyltransferase (ICMT).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein-S-isoprenylcysteine O-methyltransferase (ICMT).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein-S-isoprenylcysteine O-methyltransferase (ICMT).	[14]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Protein-S-isoprenylcysteine O-methyltransferase (ICMT).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein-S-isoprenylcysteine O-methyltransferase (ICMT).	[18]

References

• [1] Clinical translation of [(18)F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer.Eur J Nucl Med Mol Imaging. 2018 Dec;45(13):2285-2299. doi: 10.1007/s00259-018-4098-9. Epub 2018 Sep 27.
• [2] A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia.J Med Chem. 2019 Jul 11;62(13):6035-6046. doi: 10.1021/acs.jmedchem.9b00145. Epub 2019 Jun 19.
• [3] Inhibition of isoprenylcysteine carboxylmethyltransferase sensitizes common chemotherapies in cervical cancer via Ras-dependent pathway.Biomed Pharmacother. 2018 Mar;99:169-175. doi: 10.1016/j.biopha.2018.01.048. Epub 2018 Jan 11.
• [4] Isoprenylcysteine carboxylmethyltransferase regulates ovarian cancer cell response to chemotherapy and Ras activation.Biochem Biophys Res Commun. 2018 Jun 22;501(2):556-562. doi: 10.1016/j.bbrc.2018.05.038. Epub 2018 May 11.
• [5] Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT.Nature. 2018 Jan 25;553(7689):526-529. doi: 10.1038/nature25439. Epub 2018 Jan 17.
• [6] Evaluation of apoptosis imaging biomarkers in a genetic model of cell death.EJNMMI Res. 2019 Feb 19;9(1):18. doi: 10.1186/s13550-019-0487-8.
• [7] ICMT contributes to hepatocellular carcinoma growth, survival, migration and chemoresistance via multiple oncogenic pathways.Biochem Biophys Res Commun. 2019 Oct 20;518(3):584-589. doi: 10.1016/j.bbrc.2019.08.094. Epub 2019 Aug 24.
• [8] Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin 3 recycling, cell migration and cancer metastasis.Oncogene. 2017 Oct 12;36(41):5757-5767. doi: 10.1038/onc.2017.183. Epub 2017 Jun 12.
• [9] Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression.J Clin Invest. 2013 Nov;123(11):4681-94. doi: 10.1172/JCI65764.
• [10] Isoprenylcysteine carboxylmethyltransferase is associated with nasopharyngeal carcinoma chemoresistance and Ras activation.Biochem Biophys Res Commun. 2019 Aug 27;516(3):784-789. doi: 10.1016/j.bbrc.2019.06.074. Epub 2019 Jun 26.
• [11] 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.
• [12] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [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] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] 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.