Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBX300Z)

• DOT Name: Nuclear receptor coactivator 3 (NCOA3)
• Synonyms: NCoA-3; EC 2.3.1.48; ACTR; Amplified in breast cancer 1 protein; AIB-1; CBP-interacting protein; pCIP; Class E basic helix-loop-helix protein 42; bHLHe42; Receptor-associated coactivator 3; RAC-3; Steroid receptor coactivator protein 3; SRC-3; Thyroid hormone receptor activator molecule 1; TRAM-1
• Gene Name: NCOA3
• UniProt ID: NCOA3_HUMAN
• PDB ID: 1KBH; 3L3X; 3L3Z; 6ES7; 6SQC
• EC Number: 2.3.1.48
• Pfam ID: PF07469 ; PF16279 ; PF16665 ; PF08815 ; PF00989 ; PF14598 ; PF08832
• Sequence:
  MSGLGENLDPLASDSRKRKLPCDTPGQGLTCSGEKRRREQESKYIEELAELISANLSDID
  NFNVKPDKCAILKETVRQIRQIKEQGKTISNDDDVQKADVSSTGQGVIDKDSLGPLLLQA
  LDGFLFVVNRDGNIVFVSENVTQYLQYKQEDLVNTSVYNILHEEDRKDFLKNLPKSTVNG
  VSWTNETQRQKSHTFNCRMLMKTPHDILEDINASPEMRQRYETMQCFALSQPRAMMEEGE
  DLQSCMICVARRITTGERTFPSNPESFITRHDLSGKVVNIDTNSLRSSMRPGFEDIIRRC
  IQRFFSLNDGQSWSQKRHYQEAYLNGHAETPVYRFSLADGTIVTAQTKSKLFRNPVTNDR
  HGFVSTHFLQREQNGYRPNPNPVGQGIRPPMAGCNSSVGGMSMSPNQGLQMPSSRAYGLA
  DPSTTGQMSGARYGGSSNIASLTPGPGMQSPSSYQNNNYGLNMSSPPHGSPGLAPNQQNI
  MISPRNRGSPKIASHQFSPVAGVHSPMASSGNTGNHSFSSSSLSALQAISEGVGTSLLST
  LSSPGPKLDNSPNMNITQPSKVSNQDSKSPLGFYCDQNPVESSMCQSNSRDHLSDKESKE
  SSVEGAENQRGPLESKGHKKLLQLLTCSSDDRGHSSLTNSPLDSSCKESSVSVTSPSGVS
  SSTSGGVSSTSNMHGSLLQEKHRILHKLLQNGNSPAEVAKITAEATGKDTSSITSCGDGN
  VVKQEQLSPKKKENNALLRYLLDRDDPSDALSKELQPQVEGVDNKMSQCTSSTIPSSSQE
  KDPKIKTETSEEGSGDLDNLDAILGDLTSSDFYNNSISSNGSHLGTKQQVFQGTNSLGLK
  SSQSVQSIRPPYNRAVSLDSPVSVGSSPPVKNISAFPMLPKQPMLGGNPRMMDSQENYGS
  SMGGPNRNVTVTQTPSSGDWGLPNSKAGRMEPMNSNSMGRPGGDYNTSLPRPALGGSIPT
  LPLRSNSIPGARPVLQQQQQMLQMRPGEIPMGMGANPYGQAAASNQLGSWPDGMLSMEQV
  SHGTQNRPLLRNSLDDLVGPPSNLEGQSDERALLDQLHTLLSNTDATGLEEIDRALGIPE
  LVNQGQALEPKQDAFQGQEAAVMMDQKAGLYGQTYPAQGPPMQGGFHLQGQSPSFNSMMN
  QMNQQGNFPLQGMHPRANIMRPRTNTPKQLRMQLQQRLQGQQFLNQSRQALELKMENPTA
  GGAAVMRPMMQPQVSSQQGFLNAQMVAQRSRELLSHHFRQQRVAMMMQQQQQQQQQQQQQ
  QQQQQQQQQQQQQQQQTQAFSPPPNVTASPSMDGLLAGPTMPQAPPQQFPYQPNYGMGQQ
  PDPAFGRVSSPPNAMMSSRMGPSQNPMMQHPQAASIYQSSEMKGWPSGNLARNSSFSQQQ
  FAHQGNPAVYSMVHMNGSSGHMGQMNMNPMPMSGMPMGPDQKYC
• Function: Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Plays a central role in creating a multisubunit coactivator complex, which probably acts via remodeling of chromatin. Involved in the coactivation of different nuclear receptors, such as for steroids (GR and ER), retinoids (RARs and RXRs), thyroid hormone (TRs), vitamin D3 (VDR) and prostanoids (PPARs). Displays histone acetyltransferase activity. Also involved in the coactivation of the NF-kappa-B pathway via its interaction with the NFKB1 subunit.
• Tissue Specificity: Widely expressed. High expression in heart, skeletal muscle, pancreas and placenta. Low expression in brain, and very low in lung, liver and kidney.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Estrogen sig.ling pathway (hsa04915)
  Thyroid hormone sig.ling pathway (hsa04919)
  Pathways in cancer (hsa05200)
  Breast cancer (hsa05224)
• Reactome Pathway:
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Estrogen-dependent gene expression (R-HSA-9018519)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Nuclear receptor coactivator 3 (NCOA3) increases the response to substance of Calcitriol.	[24]

27 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 Nuclear receptor coactivator 3 (NCOA3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nuclear receptor coactivator 3 (NCOA3).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Nuclear receptor coactivator 3 (NCOA3).	[7]
Estrone	DM5T6US	Approved	Estrone increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[2]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[17]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Nuclear receptor coactivator 3 (NCOA3).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[1]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Nuclear receptor coactivator 3 (NCOA3).	[22]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Investigative	4-ANDROSTENE-3-17-DIONE increases the activity of Nuclear receptor coactivator 3 (NCOA3).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nuclear receptor coactivator 3 (NCOA3).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nuclear receptor coactivator 3 (NCOA3).	[18]

References

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• [5] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
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• [8] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
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• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] LC, a novel estrone-rhein hybrid compound, promotes proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells. Mol Cell Endocrinol. 2011 Sep 15;344(1-2):59-68. doi: 10.1016/j.mce.2011.06.027. Epub 2011 Jul 13.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [15] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
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• [18] 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.
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• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] Involvement of SRC-3 in deguelin-induced apoptosis in Jurkat cells. Int J Hematol. 2009 Jun;89(5):628-35. doi: 10.1007/s12185-009-0311-8. Epub 2009 Apr 14.
• [22] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [23] ErbB receptor signaling and therapeutic resistance to aromatase inhibitors. Clin Cancer Res. 2006 Feb 1;12(3 Pt 2):1008s-1012s. doi: 10.1158/1078-0432.CCR-05-2352.
• [24] Functional diversification of vitamin D receptor paralogs in teleost fish after a whole genome duplication event. Endocrinology. 2014 Dec;155(12):4641-54. doi: 10.1210/en.2014-1505. Epub 2014 Oct 3.