Details of the Drug Combination

General Information of Drug Combination (ID: DCUARDO)

Drug Combination Name
Diphenidol Gefitinib
Indication
Disease Entry Status REF
Chronic myelogenous leukemia Investigative [1]
Component Drugs Diphenidol   DMHPWOM Gefitinib   DM15F0X
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: KBM-7
Zero Interaction Potency (ZIP) Score: 18.25
Bliss Independence Score: 18.25
Loewe Additivity Score: 21.66
LHighest Single Agent (HSA) Score: 21.66

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Diphenidol
Disease Entry ICD 11 Status REF
Nausea MD90 Approved [2]
Diphenidol Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Muscarinic acetylcholine receptor M4 (CHRM4) TTQ3JTF ACM4_HUMAN Antagonist [5]
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Indication(s) of Gefitinib
Disease Entry ICD 11 Status REF
Colon adenocarcinoma N.A. Approved [3]
Glioblastoma 2A00 Approved [3]
Lung cancer 2C25.0 Approved [3]
Non-small-cell lung cancer 2C25.Y Approved [3]
Rectal adenocarcinoma 2B92 Approved [3]
Rectum mucinous adenocarcinoma N.A. Approved [3]
Solid tumour/cancer 2A00-2F9Z Approved [4]
Head and neck cancer 2D42 Phase 3 [4]
Urethral cancer 2C93 Phase 2 [4]
Colon cancer 2B90.Z Investigative [3]
Colon mucinous adenocarcinoma N.A. Investigative [3]
Gefitinib Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Epidermal growth factor receptor (EGFR) TTGKNB4 EGFR_HUMAN Inhibitor [11]
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Gefitinib Interacts with 4 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [12]
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [13]
Organic anion transporting polypeptide 1B1 (SLCO1B1) DT3D8F0 SO1B1_HUMAN Substrate [14]
Organic anion transporting polypeptide 1B3 (SLCO1B3) DT9C1TS SO1B3_HUMAN Substrate [14]
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Gefitinib Interacts with 3 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [15]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Metabolism [16]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [15]
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Gefitinib Interacts with 103 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2) OTW8V2V1 ABCG2_HUMAN Increases ADR [17]
Epidermal growth factor receptor (EGFR) OTAPLO1S EGFR_HUMAN Decreases Response To Substance [18]
Sulfhydryl oxidase 1 (QSOX1) OT4ZPK4P QSOX1_HUMAN Increases Expression [19]
Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G) OT8V1J4M GA45G_HUMAN Decreases Expression [19]
Interferon alpha-inducible protein 6 (IFI6) OTWOOAM4 IFI6_HUMAN Decreases Expression [19]
Fibroblast growth factor 6 (FGF6) OTRJ679P FGF6_HUMAN Increases Expression [19]
Ski oncogene (SKI) OT4KJ8F6 SKI_HUMAN Increases Expression [19]
Erythropoietin receptor (EPOR) OTUIOEU3 EPOR_HUMAN Increases Expression [19]
Nuclear factor NF-kappa-B p105 subunit (NFKB1) OTNRRD8I NFKB1_HUMAN Decreases Expression [19]
Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) OTDS2EAR TNR1B_HUMAN Decreases Expression [19]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A) OTDRV63V GA45A_HUMAN Increases Expression [19]
Cytochrome P450 2F1 (CYP2F1) OTY3HJH1 CP2F1_HUMAN Decreases Expression [19]
Replication protein A 70 kDa DNA-binding subunit (RPA1) OT76POLP RFA1_HUMAN Increases Expression [19]
Adenosine receptor A1 (ADORA1) OTI7X39E AA1R_HUMAN Decreases Expression [19]
14-3-3 protein sigma (SFN) OTLJCZ1U 1433S_HUMAN Decreases Expression [19]
DNA mismatch repair protein Mlh1 (MLH1) OTG5XDD8 MLH1_HUMAN Decreases Expression [19]
Glycine--tRNA ligase (GARS1) OT5B6R9Y GARS_HUMAN Increases Expression [19]
Epidermal growth factor receptor substrate 15 (EPS15) OT7NPP8U EPS15_HUMAN Increases Expression [19]
Neuronal pentraxin-2 (NPTX2) OT3SSJDP NPTX2_HUMAN Decreases Expression [19]
Leptin receptor (LEPR) OT9H7G0C LEPR_HUMAN Decreases Expression [19]
Neural retina-specific leucine zipper protein (NRL) OT65MFKQ NRL_HUMAN Decreases Expression [19]
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 (GNB2) OT3JPRCQ GBB2_HUMAN Decreases Expression [19]
Retinal guanylyl cyclase 1 (GUCY2D) OT81UJI0 GUC2D_HUMAN Decreases Expression [19]
Cell growth regulator with RING finger domain protein 1 (CGRRF1) OTLMNRCL CGRF1_HUMAN Increases Expression [19]
Dual specificity protein phosphatase 9 (DUSP9) OTZZWEQL DUS9_HUMAN Decreases Expression [19]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Activity [20]
Retinoblastoma-associated protein (RB1) OTQJUJMZ RB_HUMAN Decreases Expression [21]
Glycogen synthase kinase-3 beta (GSK3B) OTL3L14B GSK3B_HUMAN Decreases Expression [21]
Cyclin-dependent kinase 6 (CDK6) OTR95N0X CDK6_HUMAN Decreases Expression [21]
Telomerase reverse transcriptase (TERT) OT085VVA TERT_HUMAN Decreases Expression [22]
Baculoviral IAP repeat-containing protein 5 (BIRC5) OTILXZYL BIRC5_HUMAN Decreases Expression [23]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) OTVT4YA1 ATG7_HUMAN Increases Expression [24]
Myc proto-oncogene protein (MYC) OTPV5LUK MYC_HUMAN Decreases Expression [25]
Tumor necrosis factor (TNF) OT4IE164 TNFA_HUMAN Decreases Expression [7]
Interleukin-1 beta (IL1B) OT0DWXXB IL1B_HUMAN Increases Expression [26]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1) OTRGGIFP DRB1_HUMAN Affects Expression [27]
Estrogen receptor (ESR1) OTKLU61J ESR1_HUMAN Decreases Phosphorylation [28]
Receptor tyrosine-protein kinase erbB-2 (ERBB2) OTOAUNCK ERBB2_HUMAN Decreases Phosphorylation [29]
HLA class II histocompatibility antigen, DO alpha chain (HLA-DOA) OTZE5Q7R DOA_HUMAN Affects Expression [27]
Heat shock protein HSP 90-alpha (HSP90AA1) OTLG1WPK HS90A_HUMAN Increases Secretion [26]
Insulin-like growth factor 1 receptor (IGF1R) OTXJIF13 IGF1R_HUMAN Increases Phosphorylation [30]
High mobility group protein B1 (HMGB1) OT4B7CPF HMGB1_HUMAN Increases Secretion [26]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [31]
Heat shock 70 kDa protein 1A (HSPA1A) OTKGIE76 HS71A_HUMAN Increases Secretion [26]
C-C motif chemokine 2 (CCL2) OTAD2HEL CCL2_HUMAN Increases Secretion [32]
Matrix metalloproteinase-9 (MMP9) OTB2QDAV MMP9_HUMAN Decreases Expression [7]
Platelet endothelial cell adhesion molecule (PECAM1) OTXOM4D9 PECA1_HUMAN Decreases Expression [7]
Ribosomal protein S6 kinase beta-1 (RPS6KB1) OTAELNGX KS6B1_HUMAN Decreases Phosphorylation [24]
Alanine aminotransferase 1 (GPT) OTOXOA0Q ALAT1_HUMAN Increases Secretion [33]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [18]
DnaJ homolog subfamily B member 1 (DNAJB1) OTCOSEVH DNJB1_HUMAN Increases Secretion [26]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Expression [34]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Expression [34]
Caspase-1 (CASP1) OTZ3YQFU CASP1_HUMAN Increases Activity [26]
G1/S-specific cyclin-D3 (CCND3) OTNKPQ22 CCND3_HUMAN Decreases Expression [18]
HLA class I histocompatibility antigen, alpha chain F (HLA-F) OT76CM19 HLAF_HUMAN Affects Expression [27]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Phosphorylation [35]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Decreases Expression [23]
Serine/threonine-protein kinase mTOR (MTOR) OTHH8KU7 MTOR_HUMAN Decreases Phosphorylation [24]
Cyclin-dependent kinase 4 inhibitor B (CDKN2B) OTAG24N1 CDN2B_HUMAN Increases Expression [25]
Mitogen-activated protein kinase 8 (MAPK8) OTEREYS5 MK08_HUMAN Decreases Phosphorylation [7]
Cyclin-dependent kinase inhibitor 1B (CDKN1B) OTNY5LLZ CDN1B_HUMAN Increases Expression [18]
Tumor necrosis factor ligand superfamily member 6 (FASLG) OTZARCHH TNFL6_HUMAN Increases Response To Substance [36]
Cytochrome c (CYCS) OTBFALJD CYC_HUMAN Affects Localization [31]
Transcription factor E2F1 (E2F1) OTLKYBBC E2F1_HUMAN Decreases Expression [22]
Caveolin-1 (CAV1) OTEZUR1L CAV1_HUMAN Increases Expression [34]
Sequestosome-1 (SQSTM1) OTGY5D5J SQSTM_HUMAN Decreases Expression [37]
Kelch-like ECH-associated protein 1 (KEAP1) OTFHOD0C KEAP1_HUMAN Increases Expression [38]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Cleavage [36]
Cytochrome P450 1B1 (CYP1B1) OTYXFLSD CP1B1_HUMAN Decreases Activity [39]
MHC class I polypeptide-related sequence B (MICB) OTS2DVDW MICB_HUMAN Increases Expression [40]
MHC class I polypeptide-related sequence A (MICA) OTPEIEAR MICA_HUMAN Increases Expression [40]
Estrogen receptor beta (ESR2) OTXNR2WQ ESR2_HUMAN Increases Expression [41]
Serine protease HTRA1 (HTRA1) OTR8ACBF HTRA1_HUMAN Increases Expression [42]
Major histocompatibility complex class I-related gene protein (MR1) OTZU3XX7 HMR1_HUMAN Affects Expression [27]
Autophagy protein 5 (ATG5) OT4T5SMS ATG5_HUMAN Increases Expression [24]
Transcription factor SOX-17 (SOX17) OT9H4WWE SOX17_HUMAN Decreases Localization [43]
MARVEL domain-containing protein 1 (MARVELD1) OT5CPOJE MALD1_HUMAN Decreases Response To Substance [44]
GTPase KRas (KRAS) OT78QCN8 RASK_HUMAN Decreases Response To Substance [45]
Zinc finger protein SNAI2 (SNAI2) OT7Y8EJ2 SNAI2_HUMAN Affects Response To Substance [46]
Membrane-associated progesterone receptor component 1 (PGRMC1) OTBE6WAC PGRC1_HUMAN Decreases Response To Substance [47]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Increases Response To Substance [48]
Glutamate--cysteine ligase catalytic subunit (GCLC) OTESDI4D GSH1_HUMAN Affects Response To Substance [49]
RNA-binding protein 7 (RBM7) OTFIWTMF RBM7_HUMAN Affects Response To Substance [49]
Cell death regulator Aven (AVEN) OTGIN5YK AVEN_HUMAN Affects Response To Substance [49]
Forkhead box protein O3 (FOXO3) OTHXQG4P FOXO3_HUMAN Increases Response To Substance [50]
Phospholipase B-like 1 (PLBD1) OTHYEB4W PLBL1_HUMAN Affects Response To Substance [49]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Affects Response To Substance [51]
Securin (PTTG1) OTIMYS4W PTTG1_HUMAN Decreases Response To Substance [31]
Amphiregulin (AREG) OTJFOR67 AREG_HUMAN Decreases Response To Substance [49]
Pleckstrin homology-like domain family A member 2 (PHLDA2) OTMV9DPP PHLA2_HUMAN Affects Response To Substance [49]
Aurora kinase A (AURKA) OTMX0HYT AURKA_HUMAN Decreases Response To Substance [51]
DNA excision repair protein ERCC-1 (ERCC1) OTNPYQHI ERCC1_HUMAN Affects Response To Substance [10]
Bcl-2-like protein 11 (BCL2L11) OTNQQWFJ B2L11_HUMAN Increases Response To Substance [52]
Ceramide transfer protein (CERT1) OTNUCNHX CERT_HUMAN Affects Response To Substance [49]
DNA repair protein RAD51 homolog 1 (RAD51) OTNVWGC1 RAD51_HUMAN Affects Response To Substance [53]
Oncostatin-M-specific receptor subunit beta (OSMR) OTORWHPL OSMR_HUMAN Affects Response To Substance [49]
Protransforming growth factor alpha (TGFA) OTPD1LL9 TGFA_HUMAN Decreases Response To Substance [54]
Dual specificity protein phosphatase 3 (DUSP3) OTPJX9B4 DUS3_HUMAN Affects Response To Substance [49]
Transcription factor p65 (RELA) OTUJP9CN TF65_HUMAN Decreases Response To Substance [51]
Pericentrin (PCNT) OTW4Z65J PCNT_HUMAN Decreases Response To Substance [47]
Coronin-1C (CORO1C) OTXDF9T3 COR1C_HUMAN Affects Response To Substance [49]
Ribonucleoside-diphosphate reductase large subunit (RRM1) OTXGQOR9 RIR1_HUMAN Affects Response To Substance [10]
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⏷ Show the Full List of 103 DOT(s)

References

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3 Gefitinib FDA Label
4 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4941).
5 Diphenidol-related diamines as novel muscarinic M4 receptor antagonists. Bioorg Med Chem Lett. 2008 May 1;18(9):2972-6.
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14 Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
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19 Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer. Oncol Rep. 2006 Jun;15(6):1453-60.
20 Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
21 Effects and mechanisms of betulinic acid on improving EGFR TKI-resistance of lung cancer cells. Environ Toxicol. 2018 Nov;33(11):1153-1159.
22 Antiproliferative effects of gefitinib are associated with suppression of E2F-1 expression and telomerase activity. Anticancer Res. 2006 Sep-Oct;26(5A):3387-91.
23 Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells. Toxicol Appl Pharmacol. 2017 Nov 15;335:16-27. doi: 10.1016/j.taap.2017.09.017. Epub 2017 Sep 21.
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26 Reactive metabolite of gefitinib activates inflammasomes: implications for gefitinib-induced idiosyncratic reaction. J Toxicol Sci. 2020;45(11):673-680. doi: 10.2131/jts.45.673.
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28 Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat. 2006 Mar;96(2):131-46. doi: 10.1007/s10549-005-9070-2. Epub 2005 Oct 27.
29 Epidermal growth factor receptor activity determines response of colorectal cancer cells to gefitinib alone and in combination with chemotherapy. Clin Cancer Res. 2005 Oct 15;11(20):7480-9. doi: 10.1158/1078-0432.CCR-05-0328.
30 Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 2007 May 1;13(9):2795-803. doi: 10.1158/1078-0432.CCR-06-2077.
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32 Crosstalk between alveolar macrophages and alveolar epithelial cells/fibroblasts contributes to the pulmonary toxicity of gefitinib. Toxicol Lett. 2021 Mar 1;338:1-9. doi: 10.1016/j.toxlet.2020.11.011. Epub 2020 Nov 25.
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36 The anti-cancer drug gefitinib accelerates Fas-mediated apoptosis by enhancing caspase-8 activation in cancer cells. J Toxicol Sci. 2019;44(6):435-440. doi: 10.2131/jts.44.435.
37 Autophagy Inhibition Overcomes the Antagonistic Effect Between Gefitinib and Cisplatin in Epidermal Growth Factor Receptor Mutant Non--Small-Cell Lung Cancer Cells. Clin Lung Cancer. 2015 Sep;16(5):e55-66. doi: 10.1016/j.cllc.2015.03.006. Epub 2015 Apr 2.
38 Nrf2 but not autophagy inhibition is associated with the survival of wild-type epidermal growth factor receptor non-small cell lung cancer cells. Toxicol Appl Pharmacol. 2016 Nov 1;310:140-149. doi: 10.1016/j.taap.2016.09.010. Epub 2016 Sep 14.
39 Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
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42 Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
43 A high-throughput screen for teratogens using human pluripotent stem cells. Toxicol Sci. 2014 Jan;137(1):76-90. doi: 10.1093/toxsci/kft239. Epub 2013 Oct 23.
44 Inhibition of SREBP increases gefitinib sensitivity in non-small cell lung cancer cells. Oncotarget. 2016 Aug 9;7(32):52392-52403.
45 The K-Ras effector p38 MAPK confers intrinsic resistance to tyrosine kinase inhibitors by stimulating EGFR transcription and EGFR dephosphorylation. J Biol Chem. 2017 Sep 8;292(36):15070-15079. doi: 10.1074/jbc.M117.779488. Epub 2017 Jul 24.
46 Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor. Am J Respir Crit Care Med. 2011 Apr 15;183(8):1071-9. doi: 10.1164/rccm.201009-1440OC. Epub 2010 Oct 29.
47 Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance. Toxicol Appl Pharmacol. 2015 Nov 1;288(3):359-73. doi: 10.1016/j.taap.2015.08.008. Epub 2015 Aug 20.
48 Induction of CYP1A1 increases gefitinib-induced oxidative stress and apoptosis in A549 cells. Toxicol In Vitro. 2017 Oct;44:36-43.
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50 The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3169-79. doi: 10.1158/1535-7163.MCT-07-0507.
51 Aurora-A promotes gefitinib resistance via a NF-B signaling pathway in p53 knockdown lung cancer cells. Biochem Biophys Res Commun. 2011 Feb 11;405(2):168-72. doi: 10.1016/j.bbrc.2011.01.001. Epub 2011 Jan 7.
52 BIM induction of apoptosis triggered by EGFR-sensitive and resistance cell lines of non-small-cell lung cancer. Med Oncol. 2011 Jun;28(2):572-7. doi: 10.1007/s12032-010-9470-y. Epub 2010 Mar 17.
53 E3 ubiquitin ligase RNF180 reduces sensitivity of triple-negative breast cancer cells to Gefitinib by downregulating RAD51. Chem Biol Interact. 2022 Feb 25;354:109798. doi: 10.1016/j.cbi.2022.109798. Epub 2022 Jan 6.
54 Increases of amphiregulin and transforming growth factor-alpha in serum as predictors of poor response to gefitinib among patients with advanced non-small cell lung cancers. Cancer Res. 2005 Oct 15;65(20):9176-84. doi: 10.1158/0008-5472.CAN-05-1556.