Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA3Z072)

• DOT Name: CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4)
• Synonyms: Chemokine-like factor superfamily member 4
• Gene Name: CMTM4
• Related Disease:
  Clear cell renal carcinoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Male infertility
  Stomach cancer
  Hepatocellular carcinoma
  Advanced cancer
  Neoplasm
• UniProt ID: CKLF4_HUMAN
• Pfam ID: PF01284
• Sequence:
  MRSGEELDGFEGEASSTSMISGASSPYQPTTEPVSQRRGLAGLRCDPDYLRGALGRLKVA
  QVILALIAFICIETIMACSPCEGLYFFEFVSCSAFVVTGVLLIMFSLNLHMRIPQINWNL
  TDLVNTGLSAFLFFIASIVLAALNHRAGAEIAAVIFGFLATAAYAVNTFLAVQKWRVSVR
  QQSTNDYIRARTESRDVDSRPEIQRLDTFSYSTNVTVRKKSPTNLLSLNHWQLA
• Function: Acts as a backup for CMTM6 to regulate plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. May protect PD-L1/CD274 from being polyubiquitinated and targeted for degradation.
• Tissue Specificity: Highly expressed in testis and prostate.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Male infertility	DISY3YZZ	Strong	Biomarker	[4]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[14]

3 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 CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CKLF-like MARVEL transmembrane domain-containing protein 4 (CMTM4).	[16]

References

• [1] An immunophenotyping of renal clear cell carcinoma with characteristics and a potential therapeutic target for patients insensitive to immune checkpoint blockade.J Cell Biochem. 2019 Aug;120(8):13330-13341. doi: 10.1002/jcb.28607. Epub 2019 Mar 27.
• [2] CMTM4 inhibits cell proliferation and migration via AKT, ERK1/2, and STAT3 pathway in colorectal cancer.Acta Biochim Biophys Sin (Shanghai). 2019 Sep 6;51(9):915-924. doi: 10.1093/abbs/gmz084.
• [3] Systematic investigation of CMTM family genes suggests relevance to glioblastoma pathogenesis and CMTM1 and CMTM3 as priority targets.Genes Chromosomes Cancer. 2015 Jul;54(7):433-43. doi: 10.1002/gcc.22255. Epub 2015 Apr 30.
• [4] Integrated Analyses of Phenotype and Quantitative Proteome of CMTM4 Deficient Mice Reveal Its Association with Male Fertility.Mol Cell Proteomics. 2019 Jun;18(6):1070-1084. doi: 10.1074/mcp.RA119.001416. Epub 2019 Mar 13.
• [5] CMTM3, located at the critical tumor suppressor locus 16q22.1, is silenced by CpG methylation in carcinomas and inhibits tumor cell growth through inducing apoptosis.Cancer Res. 2009 Jun 15;69(12):5194-201. doi: 10.1158/0008-5472.CAN-08-3694. Epub 2009 Jun 9.
• [6] Clinical significance of CMTM4 expression in hepatocellular carcinoma.Onco Targets Ther. 2017 Nov 14;10:5439-5443. doi: 10.2147/OTT.S149786. eCollection 2017.
• [7] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] 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.