Details of the Drug Combination

General Information of Drug Combination (ID: DC0ZE8H)

• Drug Combination Name: Nintedanib + Steroid derivative 1
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  Nintedanib (DMMQ2OW): Small molecular drug
  Steroid derivative 1 (DMB0NVQ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 14.534
  Bliss Independence Score: 20.72
  Loewe Additivity Score: 1.563
  LHighest Single Agent (HSA) Score: 6.065

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Nintedanib

Disease Entry	ICD 11	Status	REF
Idiopathic pulmonary fibrosis	CB03.4	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[3]
Ovarian neoplasm	N.A.	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]

Steroid derivative 1 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Hypoxia-inducible factor 1 (HIF-1)	TTUX68I	NOUNIPROTAC	Inhibitor	[9]

Steroid derivative 1 Interacts with 27 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
G1/S-specific cyclin-E2 (CCNE2)	OTBBUKQQ	CCNE2_HUMAN	Decreases Expression	[10]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[11]
Pro-epidermal growth factor (EGF)	OTANRJ0L	EGF_HUMAN	Decreases Expression	[11]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Phosphorylation	[10]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Expression	[10]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[12]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[10]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Increases Expression	[10]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[10]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[10]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[10]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Expression	[10]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[10]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[6]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[6]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[10]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Expression	[10]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Expression	[10]
Peroxiredoxin-4 (PRDX4)	OTT4OR8G	PRDX4_HUMAN	Increases Expression	[14]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Expression	[10]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Decreases Phosphorylation	[10]
Sulfotransferase 1A1 (SULT1A1)	OT0K7JIE	ST1A1_HUMAN	Increases Sulfation	[15]
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2)	OT3K7HY5	DHB2_HUMAN	Decreases Response To Substance	[16]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Abundance	[17]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Response To Substance	[18]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Affects Chemical Synthesis	[19]

References

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• [2] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 205832
• [3] Nintedanib FDA Label
• [4] ClinicalTrials.gov (NCT04338802) Efficacy and Safety of Nintedanib in the Treatment of Pulmonary Fibrosis in Patients With Moderate to Severe COVID -19. U.S. National Institutes of Health.
• [5] Estrogen effects on tubulin expression and taxane mediated cytotoxicity in prostate cancer cells. Prostate. 2005 Oct 1;65(2):141-50. doi: 10.1002/pros.20246.
• [6] Combination of Quercetin and 2-Methoxyestradiol Enhances Inhibition of Human Prostate Cancer LNCaP and PC-3 Cells Xenograft Tumor Growth. PLoS One. 2015 May 26;10(5):e0128277. doi: 10.1371/journal.pone.0128277. eCollection 2015.
• [7] 2-Methoxyestradiol and paclitaxel have similar effects on the cell cycle and induction of apoptosis in prostate cancer cells. Cancer Lett. 2006 Jan 8;231(1):49-64. doi: 10.1016/j.canlet.2005.01.018.
• [8] Gastrointestinally distributed UDP-glucuronosyltransferase 1A10, which metabolizes estrogens and nonsteroidal anti-inflammatory drugs, depends upon phosphorylation. J Biol Chem. 2004 Jul 2;279(27):28320-9. doi: 10.1074/jbc.M401396200. Epub 2004 Apr 26.
• [9] Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015).Expert Opin Ther Pat. 2016;26(3):309-22.
• [10] 2-methoxyestradiol induces mitotic arrest, apoptosis, and synergistic cytotoxicity with arsenic trioxide in human urothelial carcinoma cells. PLoS One. 2013 Aug 13;8(8):e68703. doi: 10.1371/journal.pone.0068703. eCollection 2013.
• [11] EGF promotes HIF-1 expression in colorectal cancer cells and tumor metastasis by regulating phosphorylation of STAT3. Eur Rev Med Pharmacol Sci. 2019 Feb;23(3):1055-1062. doi: 10.26355/eurrev_201902_16993.
• [12] Expression and cyclic variations of catechol-O-methyl transferase in human endometrial stroma. Fertil Steril. 2008 Sep;90(3):789-97. doi: 10.1016/j.fertnstert.2007.01.042. Epub 2007 Apr 5.
• [13] Arsenic trioxide and 2-methoxyestradiol reduce beta-catenin accumulation after proteasome inhibition and enhance the sensitivity of myeloma cells to Bortezomib. Leuk Res. 2008 Nov;32(11):1674-83. doi: 10.1016/j.leukres.2008.03.039. Epub 2008 May 15.
• [14] Involvement of peroxiredoxin IV in the 16alpha-hydroxyestrone-induced proliferation of human MCF-7 breast cancer cells. Cell Biol Int. 2008 Apr;32(4):401-5. doi: 10.1016/j.cellbi.2007.12.009. Epub 2008 Jan 10.
• [15] Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation. Mol Pharmacol. 2006 Jun;69(6):2084-92. doi: 10.1124/mol.105.019240. Epub 2006 Mar 3.
• [16] The role of 17beta-hydroxysteroid dehydrogenases in modulating the activity of 2-methoxyestradiol in breast cancer cells. Cancer Res. 2006 Jan 1;66(1):324-30. doi: 10.1158/0008-5472.CAN-05-2391.
• [17] 12-O-tetradecanoylphorbol-13-acetate upregulates the Ah receptor and differentially alters CYP1B1 and CYP1A1 expression in MCF-7 breast cancer cells. J Cell Biochem. 1998 Sep 1;70(3):289-96.
• [18] Acquisition of resistance of pancreatic cancer cells to 2-methoxyestradiol is associated with the upregulation of manganese superoxide dismutase. Mol Cancer Res. 2012 Jun;10(6):768-77. doi: 10.1158/1541-7786.MCR-11-0378. Epub 2012 Apr 30.
• [19] In vitro model of mammary estrogen metabolism: structural and kinetic differences between catechol estrogens 2- and 4-hydroxyestradiol. Chem Res Toxicol. 2004 Sep;17(9):1258-64. doi: 10.1021/tx0498657.