Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNA51XT)

• DOT Name: Carbonic anhydrase 9 (CA9)
• Synonyms: EC 4.2.1.1; Carbonate dehydratase IX; Carbonic anhydrase IX; CA-IX; CAIX; Membrane antigen MN; P54/58N; Renal cell carcinoma-associated antigen G250; RCC-associated antigen G250; pMW1
• Gene Name: CA9
• UniProt ID: CAH9_HUMAN
• PDB ID: 2HKF; 3IAI; 5DVX; 5FL4; 5FL5; 5FL6; 6FE0; 6FE1; 6FE2; 6G98; 6G9U; 6QN2; 6QN5; 6QN6; 6QUT; 6RQN; 6RQQ; 6RQU; 6RQW; 6TL5; 6TL6; 6Y74; 7POM; 8Q18; 8Q19; 8Q1A
• EC Number: 4.2.1.1
• Pfam ID: PF00194
• Sequence:
  MAPLCPSPWLPLLIPAPAPGLTVQLLLSLLLLVPVHPQRLPRMQEDSPLGGGSSGEDDPL
  GEEDLPSEEDSPREEDPPGEEDLPGEEDLPGEEDLPEVKPKSEEEGSLKLEDLPTVEAPG
  DPQEPQNNAHRDKEGDDQSHWRYGGDPPWPRVSPACAGRFQSPVDIRPQLAAFCPALRPL
  ELLGFQLPPLPELRLRNNGHSVQLTLPPGLEMALGPGREYRALQLHLHWGAAGRPGSEHT
  VEGHRFPAEIHVVHLSTAFARVDEALGRPGGLAVLAAFLEEGPEENSAYEQLLSRLEEIA
  EEGSETQVPGLDISALLPSDFSRYFQYEGSLTTPPCAQGVIWTVFNQTVMLSAKQLHTLS
  DTLWGPGDSRLQLNFRATQPLNGRVIEASFPAGVDSSPRAAEPVQLNSCLAAGDILALVF
  GLLFAVTSVAFLVQMRRQHRRGTKGGVSYRPAEVAETGA
• Function: Catalyzes the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid (i.e. bicarbonate and hydrogen ions).
• Tissue Specificity: Expressed primarily in carcinoma cells lines. Expression is restricted to very few normal tissues and the most abundant expression is found in the epithelial cells of gastric mucosa.
• KEGG Pathway:
  Nitrogen metabolism (hsa00910)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Reversible hydration of carbon dioxide (R-HSA-1475029)
  Regulation of gene expression by Hypoxia-inducible Factor (R-HSA-1234158)

Molecular Interaction Atlas (MIA) of This DOT

26 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 Carbonic anhydrase 9 (CA9).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carbonic anhydrase 9 (CA9).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Carbonic anhydrase 9 (CA9).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Carbonic anhydrase 9 (CA9).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Carbonic anhydrase 9 (CA9).	[1]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Carbonic anhydrase 9 (CA9).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Carbonic anhydrase 9 (CA9).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Carbonic anhydrase 9 (CA9).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Carbonic anhydrase 9 (CA9).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Carbonic anhydrase 9 (CA9).	[9]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Carbonic anhydrase 9 (CA9).	[10]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Carbonic anhydrase 9 (CA9).	[11]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Carbonic anhydrase 9 (CA9).	[12]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Carbonic anhydrase 9 (CA9).	[13]
Acetazolamide	DM1AF5U	Approved	Acetazolamide decreases the activity of Carbonic anhydrase 9 (CA9).	[14]
Urethane	DM7NSI0	Phase 4	Urethane affects the expression of Carbonic anhydrase 9 (CA9).	[15]
GDC0941	DM1YAK6	Phase 2	GDC0941 decreases the expression of Carbonic anhydrase 9 (CA9).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Carbonic anhydrase 9 (CA9).	[18]
BETULINIC ACID	DMBUI2A	Phase 1	BETULINIC ACID decreases the activity of Carbonic anhydrase 9 (CA9).	[19]
GSK525762	DMPAWBN	Phase 1	GSK525762 decreases the expression of Carbonic anhydrase 9 (CA9).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Carbonic anhydrase 9 (CA9).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Carbonic anhydrase 9 (CA9).	[22]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Carbonic anhydrase 9 (CA9).	[23]
Octanal	DMTN0OK	Investigative	Octanal decreases the expression of Carbonic anhydrase 9 (CA9).	[24]
I-BET151	DMYRUH2	Investigative	I-BET151 decreases the expression of Carbonic anhydrase 9 (CA9).	[20]
Sulfate	DMW0ZBF	Investigative	Sulfate decreases the activity of Carbonic anhydrase 9 (CA9).	[25]

2 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 decreases the methylation of Carbonic anhydrase 9 (CA9).	[17]
PI-103	DMEK4TJ	Investigative	PI-103 decreases the phosphorylation of Carbonic anhydrase 9 (CA9).	[16]

References

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• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] Anthracycline inhibits recruitment of hypoxia-inducible transcription factors and suppresses tumor cell migration and cardiac angiogenic response in the host. J Biol Chem. 2012 Oct 12;287(42):34866-34882. doi: 10.1074/jbc.M112.374587. Epub 2012 Aug 20.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] Synergistic effects of arsenic trioxide and silibinin on apoptosis and invasion in human glioblastoma U87MG cell line. Neurochem Res. 2012 Feb;37(2):370-80. doi: 10.1007/s11064-011-0620-1. Epub 2011 Oct 4.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] A phase II trial with pharmacodynamic endpoints of the proteasome inhibitor bortezomib in patients with metastatic colorectal cancer. Clin Cancer Res. 2005 Aug 1;11(15):5526-33. doi: 10.1158/1078-0432.CCR-05-0081.
• [10] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [11] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [12] NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway. Int J Cancer. 2009 Jan 1;124(1):223-32. doi: 10.1002/ijc.23934.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors. J Med Chem. 2011 Oct 13;54(19):6905-18.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1 (HIF-1) pathways. J Clin Endocrinol Metab. 2011 Dec;96(12):E1934-43. doi: 10.1210/jc.2011-1426. Epub 2011 Oct 12.
• [17] 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.
• [18] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [19] Synthesis and biological investigation of new carbonic anhydrase IX (CAIX) inhibitors. Chem Biol Interact. 2018 Mar 25;284:12-23. doi: 10.1016/j.cbi.2018.02.014. Epub 2018 Feb 16.
• [20] The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer. Oncogene. 2017 Jan 5;36(1):122-132. doi: 10.1038/onc.2016.184. Epub 2016 Jun 13.
• [21] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.
• [24] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [25] Carbonic anhydrase inhibitorsInhibition of isozymes I, II, IV, V, and IX with anions isosteric and isoelectronic with sulfate, nitrate, and carbonate. Bioorg Med Chem Lett. 2005 Feb 1;15(3):567-71.