Details of the Drug Combination

General Information of Drug Combination (ID: DCOHFV6)

• Drug Combination Name: Disulfiram + Osimertinib
• Indication: Non-Small Cell Lung Cancer; Status: Phase 2 [1]
• Component Drugs:
  Disulfiram (DMCL2OK): Small molecular drug
  Osimertinib (DMRJLAT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Disulfiram

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[3]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[4]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[4]

Disulfiram Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MERS-CoV papain-like proteinase (PL-PRO)	TTYJOLE	R1AB_CVEMC (854-2740)	Inhibitor	[4]
Fatty aldehyde dehydrogenase (ALDH3A2)	TTB6UM0	AL3A2_HUMAN	Inhibitor	[8]
COVID-19 papain-like proteinase (PL-PRO)	TTNHMO8	R1AB_SARS2 (819-2763)	Inhibitor	[3]
SARS-CoV papain-like proteinase (PL-PRO)	TTRGHB2	R1AB_CVHSA (819-2740)	Inhibitor	[4]

Disulfiram Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[11]

Disulfiram Interacts with 38 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinaldehyde dehydrogenase 3 (ALDH1A3)	OT1C9NKQ	AL1A3_HUMAN	Increases ADR	[12]
Metallothionein-1F (MT1F)	OTZVUYG1	MT1F_HUMAN	Increases Expression	[13]
Metallothionein-1B (MT1B)	OTUA4FFH	MT1B_HUMAN	Increases Expression	[13]
Metallothionein-1G (MT1G)	OTAV1OCR	MT1G_HUMAN	Increases Expression	[13]
DNA replication licensing factor MCM5 (MCM5)	OTAHLB62	MCM5_HUMAN	Decreases Expression	[13]
DNA replication licensing factor MCM2 (MCM2)	OTGGORIQ	MCM2_HUMAN	Decreases Expression	[13]
Metallothionein-1X (MT1X)	OT9AKFVS	MT1X_HUMAN	Increases Expression	[13]
Transcription factor MafG (MAFG)	OTBQFUZH	MAFG_HUMAN	Increases Expression	[7]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Increases Expression	[7]
Transcription factor MafK (MAFK)	OTZJUE4P	MAFK_HUMAN	Increases Expression	[7]
Ferritin light chain (FTL)	OTYQA8A6	FRIL_HUMAN	Increases Expression	[7]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[7]
Extracellular superoxide dismutase (SOD3)	OTIOZQAB	SODE_HUMAN	Increases Expression	[7]
Aldo-keto reductase family 1 member B1 (AKR1B1)	OTRX72TH	ALDR_HUMAN	Increases Expression	[7]
Glutathione peroxidase 3 (GPX3)	OT6PK94R	GPX3_HUMAN	Increases Expression	[7]
Ferrochelatase, mitochondrial (FECH)	OTDWEI6C	HEMH_HUMAN	Increases Expression	[7]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Increases Expression	[7]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Expression	[7]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Increases Expression	[7]
SPRY domain-containing SOCS box protein 1 (SPSB1)	OTGY26U4	SPSB1_HUMAN	Increases Expression	[7]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[7]
Transcription factor MafF (MAFF)	OT9B7MX0	MAFF_HUMAN	Increases Expression	[7]
Aldehyde dehydrogenase, mitochondrial (ALDH2)	OTKJ9I3N	ALDH2_HUMAN	Decreases Activity	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[16]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[17]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[18]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Secretion	[19]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[20]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Increases Degradation	[21]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[18]
Gasdermin-D (GSDMD)	OTH39BKI	GSDMD_HUMAN	Decreases Cleavage	[22]
Hemoglobin subunit gamma-2 (HBG2)	OT4J48JJ	HBG2_HUMAN	Increases Expression	[23]
Scavenger receptor cysteine-rich type 1 protein M130 (CD163)	OT2E32LN	C163A_HUMAN	Decreases Expression	[19]
Metallothionein-1M (MT1M)	OTVT8PLU	MT1M_HUMAN	Increases Expression	[24]
C-type lectin domain family 7 member A (CLEC7A)	OTRTBH27	CLC7A_HUMAN	Increases Expression	[19]
Aldehyde dehydrogenase, dimeric NADP-preferring (ALDH3A1)	OTAYZZE6	AL3A1_HUMAN	Increases Metabolism	[25]
Ataxin-3 (ATXN3)	OTJVVGKT	ATX3_HUMAN	Increases Response To Substance	[26]

Indication(s) of Osimertinib

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Approved	[5]
Melanoma	2C30	Phase 3	[6]

Osimertinib 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	[29]

Osimertinib Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[30]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[28]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[31]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[31]

References

• [1] ClinicalTrials.gov (NCT03944772) Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
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• [6] 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: 7719).
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• [13] High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin Cancer Res. 2009 Oct 1;15(19):6070-8.
• [14] The enzymatic activity of human aldehyde dehydrogenases 1A2 and 2 (ALDH1A2 and ALDH2) is detected by Aldefluor, inhibited by diethylaminobenzaldehyde and has significant effects on cell proliferation and drug resistance. Chem Biol Interact. 2012 Jan 5;195(1):52-60.
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• [19] Comparative study of the effects of ziram and disulfiram on human monocyte-derived macrophage functions and polarization: involvement of zinc. Cell Biol Toxicol. 2021 Jun;37(3):379-400. doi: 10.1007/s10565-020-09540-6. Epub 2020 Jul 25.
• [20] Low-Dose Pesticides Alter Primary Human Bone Marrow Mesenchymal Stem/Stromal Cells through ALDH2 Inhibition. Cancers (Basel). 2021 Nov 14;13(22):5699. doi: 10.3390/cancers13225699.
• [21] Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis. 2014 Mar;35(3):692-702. doi: 10.1093/carcin/bgt366. Epub 2013 Nov 5.
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• [23] Cytochrome P(450)-dependent toxic effects of primaquine on human erythrocytes. Toxicol Appl Pharmacol. 2009 Nov 15;241(1):14-22. doi: 10.1016/j.taap.2009.07.012. Epub 2009 Jul 17.
• [24] Identification of novel activators of the metal responsive transcription factor (MTF-1) using a gene expression biomarker in a microarray compendium. Metallomics. 2020 Sep 23;12(9):1400-1415. doi: 10.1039/d0mt00071j.
• [25] Contribution of aldehyde dehydrogenase 3A1 to disulfiram penetration through monolayers consisting of cultured human corneal epithelial cells. Biol Pharm Bull. 2008 Jul;31(7):1444-8. doi: 10.1248/bpb.31.1444.
• [26] Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3. J Toxicol Sci. 2019;44(8):535-542. doi: 10.2131/jts.44.535.
• [27] In vitro inhibition of human UDP-glucuronosyltransferase (UGT) 1A1 by osimertinib, and prediction of in vivo drug-drug interactions. Toxicol Lett. 2021 Sep 15;348:10-17. doi: 10.1016/j.toxlet.2021.05.004. Epub 2021 May 24.
• [28] Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene. 2019 Jan;38(5):656-670. doi: 10.1038/s41388-018-0482-y. Epub 2018 Aug 31.
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• [30] Dihydromyricetin suppresses tumor growth via downregulation of the EGFR/Akt/survivin signaling pathway. J Biochem Mol Toxicol. 2023 Jun;37(6):e23328. doi: 10.1002/jbt.23328. Epub 2023 Feb 19.
• [31] Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. Biochem Pharmacol. 2022 Jan;195:114864. doi: 10.1016/j.bcp.2021.114864. Epub 2021 Nov 30.