Details of the Drug Combination

General Information of Drug Combination (ID: DCX7199)

• Drug Combination Name: Metformin + Hydroxychloroquine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Metformin (DM89QE1): Small molecular drug
  Hydroxychloroquine (DMSIVND): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 6.97
  Bliss Independence Score: 6.97
  Loewe Additivity Score: 21.2
  LHighest Single Agent (HSA) Score: 21.22

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metformin

Disease Entry	ICD 11	Status	REF
Colorectal carcinoma	N.A.	Approved	[2]
Non-insulin dependent diabetes	5A11	Approved	[2]
Ovarian serous cystadenocarcinoma	N.A.	Approved	[2]
Prostate carcinoma	N.A.	Approved	[2]
Type-2 diabetes	5A11	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]

Metformin Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Acetyl-CoA carboxylase 2 (ACACB)	TTY84UG	ACACB_HUMAN	Activator	[8]
Solute carrier family 47 member 1 (SLC47A1)	TTMHCGA	S47A1_HUMAN	Modulator	[9]
HUMAN mannose receptor (MRC1)	TTKV8W5	MRC1_HUMAN	Inhibitor	[4]

Metformin Interacts with 9 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[11]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[12]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[13]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[11]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[14]
Thiamine transporter 1 (SLC19A2)	DTLA4Q2	S19A2_HUMAN	Substrate	[15]
Thiamine transporter 2 (SLC19A3)	DT39CEA	S19A3_HUMAN	Substrate	[15]
Equilibrative nucleoside transporter 4 (SLC29A4)	DT3EAQP	S29A4_HUMAN	Substrate	[16]

Indication(s) of Hydroxychloroquine

Disease Entry	ICD 11	Status	REF
Chronic renal failure	GB61.Z	Approved	[5]
Malaria	1F40-1F45	Approved	[6]
Plasmodium falciparum malaria	1F40	Approved	[5]
Plasmodium malariae malaria	N.A.	Approved	[5]
Plasmodium ovale malaria	N.A.	Approved	[5]
Systemic lupus erythematosus	4A40.0	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[7]
Colon cancer	2B90.Z	Investigative	[5]

Hydroxychloroquine Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN pH-dependent viral fusion/replication (pH-DVF/R)	TTD16BI	N.A.	Inhibitor	[17]
HUMAN glycosylation of host receptor (GHR)	TTZGK1R	N.A.	Inhibitor	[17]
Toll-like receptor 7 (TLR7)	TTRJ1K4	TLR7_HUMAN	Antagonist	[18]
HUMAN toll-like receptor 7/9 signalling pathway (TLR7/9 pathway)	TT3A1EZ	N.A.	Inhibitor	[19]

Hydroxychloroquine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[20]

Hydroxychloroquine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[21]

Hydroxychloroquine Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[22]
Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3)	OTPGHZB9	IFIT3_HUMAN	Increases Expression	[23]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[24]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[23]
Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1)	OT4TMERS	NFAC1_HUMAN	Affects Expression	[25]
Claudin-1 (CLDN1)	OT27KV99	CLD1_HUMAN	Increases Expression	[26]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[23]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Increases Expression	[23]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Affects Expression	[27]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Affects Expression	[27]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[23]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Affects Localization	[28]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[29]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[30]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[30]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Degradation	[23]
CD40 ligand (CD40LG)	OT75Z6A6	CD40L_HUMAN	Decreases Expression	[25]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[24]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Expression	[23]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Activity	[28]
TNF receptor-associated factor 3 (TRAF3)	OT5TQBGV	TRAF3_HUMAN	Increases Expression	[23]
Nuclear factor of activated T-cells, cytoplasmic 2 (NFATC2)	OTK5T6HZ	NFAC2_HUMAN	Affects Localization	[25]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[31]
Interferon regulatory factor 3 (IRF3)	OT81U8ME	IRF3_HUMAN	Increases Phosphorylation	[23]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Increases Expression	[26]
Mitochondrial antiviral-signaling protein (MAVS)	OTTQ0J64	MAVS_HUMAN	Increases Expression	[23]
S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2)	OTCA9WCM	RSAD2_HUMAN	Increases Expression	[23]
Interferon-induced helicase C domain-containing protein 1 (IFIH1)	OTZA2AHA	IFIH1_HUMAN	Increases Expression	[23]
Toll-like receptor 9 (TLR9)	OTFZ45HX	TLR9_HUMAN	Decreases Expression	[32]
7-dehydrocholesterol reductase (DHCR7)	OTLILBUI	DHCR7_HUMAN	Affects Expression	[27]

References

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• [5] Hydroxychloroquine FDA Label
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• [25] Hydroxychloroquine inhibits CD154 expression in CD4(+) T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signaling. Arthritis Res Ther. 2017 Aug 9;19(1):183. doi: 10.1186/s13075-017-1393-y.
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