Details of the Drug Combination

General Information of Drug Combination (ID: DCUMH4Q)

• Drug Combination Name: Flavonoid derivative 1 + Fomepizole
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Flavonoid derivative 1 (DMCQP0B): Small molecular drug
  Fomepizole (DM6VOWQ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 4.5
  Bliss Independence Score: 4.5
  Loewe Additivity Score: 6.29
  LHighest Single Agent (HSA) Score: 6.3

Molecular Interaction Atlas of This Drug Combination

Flavonoid derivative 1 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Signal transducer and activator of transcription 3 (STAT3)	TTH8FZW	STAT3_HUMAN	Inhibitor	[8]

Flavonoid derivative 1 Interacts with 76 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Decreases Phosphorylation	[9]
Amine oxidase A (MAOA)	OT8NIWMQ	AOFA_HUMAN	Decreases Activity	[10]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Increases Expression	[11]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[12]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[12]
Tumor protein p73 (TP73)	OT0LUO47	P73_HUMAN	Increases Expression	[13]
Prostate stem cell antigen (PSCA)	OTQ574EY	PSCA_HUMAN	Decreases Expression	[13]
Growth arrest and DNA damage-inducible protein GADD45 beta (GADD45B)	OTL9I7LO	GA45B_HUMAN	Increases Expression	[13]
CCN family member 5 (CCN5)	OTADU8JJ	CCN5_HUMAN	Decreases Expression	[6]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Increases Expression	[14]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[15]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Decreases Activity	[16]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[14]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Affects Binding	[17]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Expression	[18]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Affects Activity	[19]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Expression	[20]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[5]
HLA class II histocompatibility antigen gamma chain (CD74)	OTO16X4Q	HG2A_HUMAN	Decreases Expression	[21]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[22]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[16]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[15]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[23]
Fructose-1,6-bisphosphatase 1 (FBP1)	OTQBANEP	F16P1_HUMAN	Decreases Expression	[13]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[14]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[24]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[25]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Increases Expression	[25]
Pyruvate kinase PKM (PKM)	OTLHHMC2	KPYM_HUMAN	Increases Activity	[26]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[13]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Secretion	[27]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[28]
Transcription factor JunB (JUNB)	OTG2JXV5	JUNB_HUMAN	Decreases Activity	[16]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Decreases Activity	[16]
Early growth response protein 1 (EGR1)	OTCP6XGZ	EGR1_HUMAN	Increases Expression	[6]
Cadherin-2 (CDH2)	OTH0Y56P	CADH2_HUMAN	Decreases Expression	[25]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[15]
Nuclear receptor subfamily 1 group D member 1 (NR1D1)	OTJ38PTB	NR1D1_HUMAN	Decreases Expression	[6]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Activity	[29]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[30]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[30]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[15]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Increases Expression	[13]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Activity	[31]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[5]
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Decreases Expression	[14]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Expression	[14]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[6]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[32]
Cyclin-dependent kinase 4 inhibitor C (CDKN2C)	OTCLOV90	CDN2C_HUMAN	Decreases Expression	[13]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[33]
Mitogen-activated protein kinase 9 (MAPK9)	OTCEVJ9E	MK09_HUMAN	Increases Phosphorylation	[33]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[29]
Serine/threonine-protein kinase PLK1 (PLK1)	OTRZX45T	PLK1_HUMAN	Decreases Expression	[15]
Protein FosB (FOSB)	OTW6C05J	FOSB_HUMAN	Decreases Activity	[16]
Mitogen-activated protein kinase 10 (MAPK10)	OTC46VX1	MK10_HUMAN	Increases Phosphorylation	[33]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[32]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[33]
Sestrin-2 (SESN2)	OT889IXY	SESN2_HUMAN	Increases Expression	[34]
Focal adhesion kinase 1 (PTK2)	OT3Q1JDY	FAK1_HUMAN	Decreases Phosphorylation	[27]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[33]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[33]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[28]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Increases Expression	[5]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Activity	[35]
Solute carrier family 22 member 6 (SLC22A6)	OTKRCBVM	S22A6_HUMAN	Decreases Activity	[36]
Quinone oxidoreductase PIG3 (TP53I3)	OTSCM68G	QORX_HUMAN	Increases Expression	[13]
Dehydrogenase/reductase SDR family member 11 (DHRS11)	OTU3J0ZL	DHR11_HUMAN	Decreases Activity	[37]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Decreases Activity	[36]
Estrogen receptor beta (ESR2)	OTXNR2WQ	ESR2_HUMAN	Increases Activity	[38]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Increases Expression	[5]
Tumor protein 63 (TP63)	OT0WOOKQ	P63_HUMAN	Increases Expression	[13]
Serine/threonine-protein kinase TBK1 (TBK1)	OT1P06NV	TBK1_HUMAN	Decreases Activity	[39]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Activity	[22]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Decreases Activity	[40]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Response To Substance	[28]

Indication(s) of Fomepizole

Disease Entry	ICD 11	Status	REF
Athylene glycol or methanol poisoning	NE61	Approved	[2]

Fomepizole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Alcohol dehydrogenase 1A (ADH1A)	TT5AHZ0	ADH1A_HUMAN	Modulator	[41]

Fomepizole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[42]

Fomepizole Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Activity	[43]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [3] Inhibition of cell growth and VEGF expression in ovarian cancer cells by flavonoids. Nutr Cancer. 2008;60(6):800-9.
• [4] Structure-dependent modulation of aryl hydrocarbon receptor-mediated activities by flavonoids. Toxicol Sci. 2018 Jul 1;164(1):205-217.
• [5] Antitumor activity of luteolin in human colon cancer SW620 cells is mediated by the ERK/FOXO3a signaling pathway. Toxicol In Vitro. 2020 Aug;66:104852. doi: 10.1016/j.tiv.2020.104852. Epub 2020 Apr 5.
• [6] Cytotoxicity of flavones and flavonols to a human esophageal squamous cell carcinoma cell line (KYSE-510) by induction of G2/M arrest and apoptosis. Toxicol In Vitro. 2009 Aug;23(5):797-807. doi: 10.1016/j.tiv.2009.04.007. Epub 2009 May 3.
• [7] Genetic variants of human UGT1A3: functional characterization and frequency distribution in a Chinese Han population. Drug Metab Dispos. 2006 Sep;34(9):1462-7. doi: 10.1124/dmd.106.009761. Epub 2006 May 31.
• [8] A STAT inhibitor patent review: progress since 2011.Expert Opin Ther Pat. 2015;25(12):1397-421.
• [9] Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3. Chem Biol Interact. 2014 Apr 25;213:60-8. doi: 10.1016/j.cbi.2014.02.002. Epub 2014 Feb 11.
• [10] Evaluation of the inhibitory effects of quercetin-related flavonoids and tea catechins on the monoamine oxidase-A reaction in mouse brain mitochondria. J Agric Food Chem. 2012 Oct 17;60(41):10270-7.
• [11] Benzo[a]pyrene sensitizes MCF7 breast cancer cells to induction of G1 arrest by the natural flavonoid eupatorin-5-methyl ether, via activation of cell signaling proteins and CYP1-mediated metabolism. Toxicol Lett. 2014 Oct 15;230(2):304-13.
• [12] Drug interaction study of flavonoids toward CYP3A4 and their quantitative structure activity relationship (QSAR) analysis for predicting potential effects. Toxicol Lett. 2018 Sep 15;294:27-36.
• [13] Flavones and flavonols exert cytotoxic effects on a human oesophageal adenocarcinoma cell line (OE33) by causing G2/M arrest and inducing apoptosis. Food Chem Toxicol. 2008 Jun;46(6):2042-53. doi: 10.1016/j.fct.2008.01.049. Epub 2008 Feb 7.
• [14] The PPAR-dependent effect of flavonoid luteolin against damage induced by the chemotherapeutic irinotecan in human intestinal cells. Chem Biol Interact. 2022 Jan 5;351:109712. doi: 10.1016/j.cbi.2021.109712. Epub 2021 Oct 23.
• [15] Luteolin exerts anti-tumor activity through the suppression of epidermal growth factor receptor-mediated pathway in MDA-MB-231 ER-negative breast cancer cells. Food Chem Toxicol. 2012 Nov;50(11):4136-43. doi: 10.1016/j.fct.2012.08.025. Epub 2012 Aug 20.
• [16] Luteolin, a flavonoid, inhibits AP-1 activation by basophils. Biochem Biophys Res Commun. 2006 Feb 3;340(1):1-7. doi: 10.1016/j.bbrc.2005.11.157. Epub 2005 Dec 6.
• [17] Recombinant human estrogen, androgen and progesterone receptors for detection of potential endocrine disruptors. Anal Bioanal Chem. 2004 Feb;378(3):664-9. doi: 10.1007/s00216-003-2251-0. Epub 2003 Oct 25.
• [18] The flavonoids apigenin and luteolin suppress ultraviolet A-induced matrix metalloproteinase-1 expression via MAPKs and AP-1-dependent signaling in HaCaT cells. J Dermatol Sci. 2011 Jan;61(1):23-31. doi: 10.1016/j.jdermsci.2010.10.016. Epub 2010 Nov 9.
• [19] Luteolin as a glycolysis inhibitor offers superior efficacy and lesser toxicity of doxorubicin in breast cancer cells. Biochem Biophys Res Commun. 2008 Aug 1;372(3):497-502. doi: 10.1016/j.bbrc.2008.05.080. Epub 2008 May 27.
• [20] Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy. 2000 Apr;30(4):501-8. doi: 10.1046/j.1365-2222.2000.00768.x.
• [21] Suppressive Effects of Selected Food Phytochemicals on CD74 Expression in NCI-N87 Gastric Carcinoma Cells. J Clin Biochem Nutr. 2008 Sep;43(2):109-17. doi: 10.3164/jcbn.2008054.
• [22] Luteolin enhances the bioavailability of benzo(a)pyrene in human colon carcinoma cells. Arch Biochem Biophys. 2010 Jun 15;498(2):111-8. doi: 10.1016/j.abb.2010.04.009. Epub 2010 Apr 18.
• [23] Structure-activity relationship and mechanism of flavonoids on the inhibitory activity of P-glycoprotein (P-gp)-mediated transport of rhodamine123 and daunorubicin in P-gp overexpressed human mouth epidermal carcinoma (KB/MDR) cells. Food Chem Toxicol. 2021 Sep;155:112381. doi: 10.1016/j.fct.2021.112381. Epub 2021 Jul 1.
• [24] Blockade of the epidermal growth factor receptor tyrosine kinase activity by quercetin and luteolin leads to growth inhibition and apoptosis of pancreatic tumor cells. Anticancer Res. 2002 May-Jun;22(3):1615-27.
• [25] Luteolin exerts pro-apoptotic effect and anti-migration effects on A549 lung adenocarcinoma cells through the activation of MEK/ERK signaling pathway. Chem Biol Interact. 2016 Sep 25;257:26-34. doi: 10.1016/j.cbi.2016.07.028. Epub 2016 Jul 26.
• [26] In vitro effects of some flavones on human pyruvate kinase isoenzyme M2. J Biochem Mol Toxicol. 2015 Mar;29(3):109-13. doi: 10.1002/jbt.21673. Epub 2014 Nov 11.
• [27] Transinactivation of the epidermal growth factor receptor tyrosine kinase and focal adhesion kinase phosphorylation by dietary flavonoids: effect on invasive potential of human carcinoma cells. Biochem Pharmacol. 2004 Jun 1;67(11):2103-14. doi: 10.1016/j.bcp.2004.02.023.
• [28] The genotoxicity potential of luteolin is enhanced by CYP1A1 and CYP1A2 in human lymphoblastoid TK6 cells. Toxicol Lett. 2021 Jun 15;344:58-68. doi: 10.1016/j.toxlet.2021.03.006. Epub 2021 Mar 13.
• [29] Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1. Biochem Pharmacol. 2001 May 15;61(10):1205-15. doi: 10.1016/s0006-2952(01)00583-4.
• [30] Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells. Cancer Lett. 2009 Aug 28;281(2):162-70. doi: 10.1016/j.canlet.2009.02.041. Epub 2009 Apr 2.
• [31] Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2. Biochem Pharmacol. 2005 Feb 15;69(4):699-708. doi: 10.1016/j.bcp.2004.11.002. Epub 2004 Dec 23.
• [32] Inhibition of cell survival, invasion, tumor growth and histone deacetylase activity by the dietary flavonoid luteolin in human epithelioid cancer cells. Eur J Pharmacol. 2011 Jan 25;651(1-3):18-25. doi: 10.1016/j.ejphar.2010.10.063. Epub 2010 Nov 11.
• [33] Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. Toxicol In Vitro. 2011 Oct;25(7):1385-91. doi: 10.1016/j.tiv.2011.05.009. Epub 2011 May 13.
• [34] Luteolin prevents liver from tunicamycin-induced endoplasmic reticulum stress via nuclear factor erythroid 2-related factor 2-dependent sestrin 2 induction. Toxicol Appl Pharmacol. 2020 Jul 15;399:115036. doi: 10.1016/j.taap.2020.115036. Epub 2020 May 11.
• [35] The antioxidant quercetin inhibits cellular proliferation via HIF-1-dependent induction of p21WAF. Antioxid Redox Signal. 2010 Aug 15;13(4):437-48. doi: 10.1089/ars.2009.3000.
• [36] Potent Inhibitors of Organic Anion Transporters 1 and 3 From Natural Compounds and Their Protective Effect on Aristolochic Acid Nephropathy. Toxicol Sci. 2020 Jun 1;175(2):279-291. doi: 10.1093/toxsci/kfaa033.
• [37] Rabbit dehydrogenase/reductase SDR family member 11 (DHRS11): Its identity with acetohexamide reductase with broad substrate specificity and inhibitor sensitivity, different from human DHRS11. Chem Biol Interact. 2019 May 25;305:12-20. doi: 10.1016/j.cbi.2019.03.026. Epub 2019 Mar 26.
• [38] In vitro estrogenic activity of Achillea millefolium L. Phytomedicine. 2007 Feb;14(2-3):147-52. doi: 10.1016/j.phymed.2006.05.005. Epub 2006 Jul 24.
• [39] Suppression of the TRIF-dependent signaling pathway of Toll-like receptors by luteolin. Biochem Pharmacol. 2009 Apr 15;77(8):1391-400. doi: 10.1016/j.bcp.2009.01.009. Epub 2009 Jan 23.
• [40] Drug interaction study of flavonoids toward OATP1B1 and their 3D structure activity relationship analysis for predicting hepatoprotective effects. Toxicology. 2020 May 15;437:152445. doi: 10.1016/j.tox.2020.152445. Epub 2020 Apr 4.
• [41] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [42] Treatment of patients with ethylene glycol or methanol poisoning: focus on fomepizole. Open Access Emerg Med. 2010 Aug 24;2:67-75.
• [43] Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur J Drug Metab Pharmacokinet. 2011 Mar;36(1):1-16.