Details of Drug Off-Target (DOT)

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

• DOT Name: Chromodomain-helicase-DNA-binding protein 9 (CHD9)
• Synonyms: CHD-9; EC 3.6.4.12; ATP-dependent helicase CHD9; Chromatin-related mesenchymal modulator; CReMM; Chromatin-remodeling factor CHROM1; Kismet homolog 2; PPAR-alpha-interacting complex protein 320 kDa; Peroxisomal proliferator-activated receptor A-interacting complex 320 kDa protein
• Gene Name: CHD9
• Related Disease:
  Colorectal carcinoma
  Neoplasm
  Myocardial ischemia
  Werner syndrome
  Advanced cancer
  Neuroblastoma
• UniProt ID: CHD9_HUMAN
• EC Number: 3.6.4.12
• Pfam ID: PF07533 ; PF00385 ; PF00271 ; PF00176
• Sequence:
  MTDPMMDFFDDANLFGETLEGLSDDAFVQPGPVSLVDELNLGAEFEPLHIDSLNHVQGTP
  THQKMTDFEQLNQFDSIKFHHVNQSFGSPAEHVLSPHSQFNCSPIHPQNQPNGLFPDVSD
  GSPMWGHQTATTISNQNGSPFHQQGHSHSMHQNKSFVAHHDFALFQANEQQTQCTSLRSQ
  QNRNNLNPGQNSLSQSKNFMNVSGPHRVNVNHPPQMTNASNSQQSISMQQFSQTSNPSAH
  FHKCSSHQEGNFNGPSPNMTSCSVSNSQQFSSHYSFSSNHISPNSLLQSSAVLASNHTNQ
  TLSDFTGSNSFSPHRGIKQESTQHILNPNTSLNSNNFQILHSSHPQGNYSNSKLSPVHMN
  FPDPVDSGTQMGHFNDHVETNGFSSLEENLLHQVESQTEPFTGLDPEDLLQEGLLPHFDE
  STFGQDNSSHILDHDLDRQFTSHLVTRPSDMAQTQLQSQARSWHSSFSNHQHLHDRNHLC
  LQRQPPSSKKSDGSGTYTKLQNTQVRVMSEKKQRKKVESESKQEKANRIISEAIAKAKER
  GERNIPRVMSPENFPTASVEGKEEKKGRRMKSKPKDKDSKKTKTCSKLKEKTKIGKLIIT
  LGKKQKRKNESSDEISDAEQMPQHTLKDQDSQKRRSNRQIKRKKYAEDIEGKQSEEEVKG
  SMKIKKNSAPLPGEQPLQLFVENPSEEDAAIVDKILSSRTVKKEISPGVMIDTEEFFVKY
  KNYSYLHCEWATEEQLLKDKRIQQKIKRFKLRQAQRAHFFADMEEEPFNPDYVEVDRVLE
  VSFCEDKDTGEPVIYYLVKWCSLPYEDSTWELKEDVDLAKIEEFEQLQASRPDTRRLDRP
  PSNIWKKIDQSRDYKNGNQLREYQLEGLNWLLFNWYNRRNCILADEMGLGKTIQSITFLY
  EILLTGIRGPFLIIAPLSTIANWEREFRTWTDINVVVYHGSLISRQMIQQYEMYFRDSQG
  RIIRGAYRFQAIITTFEMILGGCGELNAIEWRCVIIDEAHRLKNKNCKLLEGLKLMNLEH
  KVLLTGTPLQNTVEELFSLLHFLEPLRFPSESTFMQEFGDLKTEEQVQKLQAILKPMMLR
  RLKEDVEKKLAPKEETIIEVELTNIQKKYYRAILEKNFSFLSKGAGQTNVPNLVNTMMEL
  RKCCNHPYLIKGAEEKILGEFRDTYNPAASDFHLQAMIQSAGKLVLIDKLLPKMKAGGHK
  VLIFSQMVRCLDILEDYLIHKRYLYERIDGRVRGNLRQAAIDRFSKPDSDRFVFLLCTRA
  GGLGINLTAADTCIIFDSDWNPQNDLQAQARCHRIGQNKAVKVYRLVTRNSYEREMFDRA
  SLKLGLDKAVLQSMSGRESNVGGIQQLSKKEIEDLLRRGAYGAIMEEEDEGSKFCEEDID
  QILLRRTKTITIESEGRGSTFAKASFVASGNRTDISLDDPNFWQKWAKKAEIDIEAISGR
  NSLVIDTPRIRKQTRPFSATKDELAELSEAESEGDEKPKLRRPCDRSNGYGRTECFRVEK
  NLLVYGWGRWREILSHGRFKRQLNEHDVEIICRALLAYCLVHYRGDEKIKGFIWDLITPT
  EDGQTRELQNHLGLSAPVPRGRKGKKVKTQTSSFDIQKAEWLRKYNPEQLLQDEGYKKHI
  KHHCNKVLLRVRMLYYLKQEVIGNECQKVFDGVDASDIDVWVPEPDHSEVPAEWWDFDAD
  KSLLIGVFKHGYEKYNTIRADPALCFLERVGKPDEKAVAAEQRANDYMDGDVEDPEYKPA
  PAIFKDDIEDDVSSPGDLVIADGDGQLMEGDKVYWPTQSALTTRLRRLITAYQRTNKNRQ
  IQQIQPTFSVPTSVMQPIYEEATLNPKMAAKIERQQRWTRREEADFYRVVSTFGVVFDPD
  RGQFDWTKFRAMARLHKKTDDSLEKYLYAFMSMCRRVCRLPSKEELVDPNIFIQPITEER
  ASRTLYRIELLRKVREQALRHPQLFERLKLCHPNPDLPVWWECGPHDRDLLIGAAKHGVS
  RTDYHILRDPELSFMAAQRNYSQSKMAHSRTSTPLLQQYQVALSASPLTSLPRLLDAKGI
  ILEEMKVKSENLKEEPQSSEEESMSSVETRTLIKSEPVSPKNGVLPQATGDQKSGGKCET
  DRRMVAARTEPLTPNPASKKPRVHKRGSESSSDSDSDSERSSCSSRSSSSSSSSSCSHSR
  SGSSSSSSSSCSSASSSSSSSTSSSSSSSSSSSEESDSDEEEAQKRESTTHMKAYDEESV
  ASLSTTQDETQDSFQMNNGTPESAYILQGGYMLAASYWPKDRVMINRLDSICQTVLKGKW
  PSARRSYDANTVASFYTTKLLDSPGAATEYSDPSVPTPPGAGVKEEHDQSTQMSKVKKHV
  REKEFTVKIKDEGGLKLTFQKQGLAQKRPFDGEDGALGQQQYLTRLRELQSASETSLVNF
  PKSIPVSGTSIQPTLGANGVILDNQPIVKKRRGRRKNVEGVDIFFFNRNKPPNHVSLGLT
  SSQISTGINPALSYTQPQGIPDTESPVPVINLKDGTRLAGDDAPKRKDLEKWLKEHPGYV
  EDLGAFIPRMQLHEGRPKQKRHRCRNPNKLDVNSLTGEERVQLINRRNARKVGGAFAPPL
  KDLCRFLKENSEYGVAPEWGDVVKQSGFLPESMYERILTGPVVREEVSRRGRRPKSGIAK
  ATAAAAAASATSVSGNPLLANGLLPGVDLTTLQALQQNLQNLQSLQVTAGLMGMPTGLPS
  GGEAKNMAAMFPMLLSGMAGLPNLLGMGGLLTKPTESGTEDKKGSDSKESEGKTERTESQ
  SSENGGENSVSSSPSTSSTAALNTAAAANPLALNPLLLSNILYPGMLLTPGLNLHIPTLS
  QSNTFDVQNKNSDLGSSKSVEVKEEDSRIKDQEDKGGTEPSPLNENSTDEGSEKADASSG
  SDSTSSSSEDSDSSNED
• Function: Acts as a transcriptional coactivator for PPARA and possibly other nuclear receptors. Proposed to be a ATP-dependent chromatin remodeling protein. Has DNA-dependent ATPase activity and binds to A/T-rich DNA. Associates with A/T-rich regulatory regions in promoters of genes that participate in the differentiation of progenitors during osteogenesis.
• Tissue Specificity: Widely expressed at low levels. In bone marrow, expression is restricted to osteoprogenitor cells adjacent to mature osteoblasts.
• Reactome Pathway:
  BMAL1 (R-HSA-1368108)
  PPARA activates gene expression (R-HSA-1989781)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Regulation of lipid metabolism by PPARalpha (R-HSA-400206)
  Circadian Clock (R-HSA-400253)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  Heme signaling (R-HSA-9707616)
  RORA activates gene expression (R-HSA-1368082)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[2]
Werner syndrome	DISZY45W	moderate	Biomarker	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[4]

3 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 Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[11]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[14]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Chromodomain-helicase-DNA-binding protein 9 (CHD9).	[19]

References

• [1] Decreased expression of chromodomain helicase DNA-binding protein 9 is a novel independent prognostic biomarker for colorectal cancer.Braz J Med Biol Res. 2018 Jul 23;51(9):e7588. doi: 10.1590/1414-431X20187588.
• [2] MicroRNA-208a Regulates H9c2 Cells Simulated Ischemia-Reperfusion Myocardial Injury via Targeting CHD9 through Notch/NF-kappa B Signal Pathways.Int Heart J. 2018 May 30;59(3):580-588. doi: 10.1536/ihj.17-147. Epub 2018 May 20.
• [3] miR-200c-3p spreads invasive capacity in human oral squamous cell carcinoma microenvironment.Mol Carcinog. 2018 Feb;57(2):295-302. doi: 10.1002/mc.22744. Epub 2017 Oct 31.
• [4] Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression.Oncotarget. 2016 Apr 19;7(16):21840-52. doi: 10.18632/oncotarget.8187.
• [5] 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.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] 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.
• [8] 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.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] 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.
• [12] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] 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.