Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBGWU86)

• DOT Name: Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1)
• Synonyms: Zinc finger protein 828
• Gene Name: CHAMP1
• Related Disease:
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal dominant 40
  Cardiac failure
  Congestive heart failure
  Intellectual disability
  Non-small-cell lung cancer
  Type-1/2 diabetes
  Sarcoma
  Soft tissue sarcoma
  Autosomal dominant non-syndromic intellectual disability
  Fibromatosis
  Leiomyosarcoma
  Multi-drug resistant tuberculosis
  Neoplasm
  Tuberculosis
• UniProt ID: CHAP1_HUMAN
• PDB ID: 5XPT; 5XPU; 6EKJ; 6EKL
• Sequence:
  MEAFQELRKPSARLECDHCSFRGTDYENVQIHMGTIHPEFCDEMDAGGLGKMIFYQKSAK
  LFHCHKCFFTSKMYSNVYYHITSKHASPDKWNDKPKNQLNKETDPVKSPPLPEHQKIPCN
  SAEPKSIPALSMETQKLGSVLSPESPKPTPLTPLEPQKPGSVVSPELQTPLPSPEPSKPA
  SVSSPEPPKSVPVCESQKLAPVPSPEPQKPAPVSPESVKATLSNPKPQKQSHFPETLGPP
  SASSPESPVLAASPEPWGPSPAASPESRKSARTTSPEPRKPSPSESPEPWKPFPAVSPEP
  RRPAPAVSPGSWKPGPPGSPRPWKSNPSASSGPWKPAKPAPSVSPGPWKPIPSVSPGPWK
  PTPSVSSASWKSSSVSPSSWKSPPASPESWKSGPPELRKTAPTLSPEHWKAVPPVSPELR
  KPGPPLSPEIRSPAGSPELRKPSGSPDLWKLSPDQRKTSPASLDFPESQKSSRGGSPDLW
  KSSFFIEPQKPVFPETRKPGPSGPSESPKAASDIWKPVLSIDTEPRKPALFPEPAKTAPP
  ASPEARKRALFPEPRKHALFPELPKSALFSESQKAVELGDELQIDAIDDQKCDILVQEEL
  LASPKKLLEDTLFPSSKKLKKDNQESSDAELSSSEYIKTDLDAMDIKGQESSSDQEQVDV
  ESIDFSKENKMDMTSPEQSRNVLQFTEEKEAFISEEEIAKYMKRGKGKYYCKICCCRAMK
  KGAVLHHLVNKHNVHSPYKCTICGKAFLLESLLKNHVAAHGQSLLKCPRCNFESNFPRGF
  KKHLTHCQSRHNEEANKKLMEALEPPLEEQQI
• Function: Required for proper alignment of chromosomes at metaphase and their accurate segregation during mitosis. Involved in the maintenance of spindle microtubules attachment to the kinetochore during sister chromatid biorientation. May recruit CENPE and CENPF to the kinetochore.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[6]
Sarcoma	DISZDG3U	moderate	Genetic Variation	[7]
Soft tissue sarcoma	DISSN8XB	moderate	Genetic Variation	[7]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[8]
Fibromatosis	DIS7535C	Limited	Genetic Variation	[9]
Leiomyosarcoma	DIS6COXM	Limited	Biomarker	[10]
Multi-drug resistant tuberculosis	DIS1A2CS	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[12]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[11]

5 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 Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[18]
Marinol	DM70IK5	Approved	Marinol increases the expression of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Chromosome alignment-maintaining phosphoprotein 1 (CHAMP1).	[22]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioural phenotype. Brain Commun. 2022 Aug 30;4(5):fcac220. doi: 10.1093/braincomms/fcac220. eCollection 2022.
• [3] Comparison of Hydralazine/Nitrate and Angiotensin Receptor Neprilysin Inhibitor Use Among Black Versus Nonblack Americans With Heart Failure and Reduced Ejection Fraction (from CHAMP-HF).Am J Cardiol. 2019 Dec 15;124(12):1900-1906. doi: 10.1016/j.amjcard.2019.09.020. Epub 2019 Sep 26.
• [4] De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability.Hum Mutat. 2016 Apr;37(4):354-8. doi: 10.1002/humu.22952. Epub 2016 Feb 4.
• [5] CHAMP: A Phase II Study of Panitumumab With Pemetrexed and Cisplatin Versus Pemetrexed and Cisplatin in the Treatment of Patients With Advanced-Stage Primary Nonsquamous Non-Small-Cell Lung Cancer With Particular Regard to the KRAS Status.Clin Lung Cancer. 2015 Nov;16(6):447-56. doi: 10.1016/j.cllc.2015.05.009. Epub 2015 Jun 2.
• [6] Statin Therapy and Risk of Incident Diabetes Mellitus in Adults With Cardiovascular Risk Factors.Am J Cardiol. 2020 Feb 15;125(4):534-541. doi: 10.1016/j.amjcard.2019.11.011. Epub 2019 Nov 19.
• [7] Cytogenetic analysis of 46 pleomorphic soft tissue sarcomas and correlation with morphologic and clinical features: a report of the CHAMP Study Group. Chromosomes and MorPhology.Genes Chromosomes Cancer. 1998 May;22(1):16-25. doi: 10.1002/(sici)1098-2264(199805)22:1<16::aid-gcc3>3.0.co;2-a.
• [8] De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment. Am J Hum Genet. 2015 Sep 3;97(3):493-500. doi: 10.1016/j.ajhg.2015.08.003.
• [9] Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology.Mod Pathol. 2000 Oct;13(10):1080-5. doi: 10.1038/modpathol.3880200.
• [10] Comparative cytogenetic study of spindle cell and pleomorphic leiomyosarcomas of soft tissues: a report from the CHAMP Study Group.Cancer Genet Cytogenet. 2000 Jan 1;116(1):66-73. doi: 10.1016/s0165-4608(99)00114-4.
• [11] Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP).Trials. 2018 Dec 20;19(1):693. doi: 10.1186/s13063-018-3070-0.
• [12] Combined morphologic and karyotypic study of 59 atypical lipomatous tumors. Evaluation of their relationship and differential diagnosis with other adipose tissue tumors (a report of the CHAMP Study Group).Am J Surg Pathol. 1996 Oct;20(10):1182-9. doi: 10.1097/00000478-199610000-00002.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [17] 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.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [20] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [21] 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.
• [22] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.