Details of the Drug Combination

General Information of Drug Combination (ID: DCOXPYX)

• Drug Combination Name: Proguanil + NVP-AUY922
• Indication: Hepatoblastoma; Status: Investigative [1]
• Component Drugs:
  Proguanil (DMBL79I): Small molecular drug
  NVP-AUY922 (DMTYXQF): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HB3
  Zero Interaction Potency (ZIP) Score: 10.963
  Bliss Independence Score: 2.594
  Loewe Additivity Score: 6.994
  LHighest Single Agent (HSA) Score: 1.594

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Proguanil

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[2]

Proguanil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Polypeptide deformylase (PDF)	TT9SL3Q	DEFM_HUMAN	Inhibitor	[5]

Proguanil Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[7]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[8]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[9]

Proguanil Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[10]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[10]

Indication(s) of NVP-AUY922

Disease Entry	ICD 11	Status	REF
Multiple myeloma	2A83	Phase 2	[3]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]

NVP-AUY922 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Heat shock protein 90 alpha (HSP90A)	TT78R5H	HS90A_HUMAN	Inhibitor	[12]

NVP-AUY922 Interacts with 35 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Anterior gradient protein 2 homolog (AGR2)	OTRRZT7W	AGR2_HUMAN	Increases Expression	[11]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[13]
Fibroblast growth factor 1 (FGF1)	OT8I64X8	FGF1_HUMAN	Decreases Expression	[11]
ATP synthase subunit beta, mitochondrial (ATP5F1B)	OTLFZUQK	ATPB_HUMAN	Decreases Expression	[11]
Insulin-like growth factor 1 receptor (IGF1R)	OTXJIF13	IGF1R_HUMAN	Decreases Expression	[13]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Decreases Expression	[13]
Platelet-derived growth factor receptor beta (PDGFRB)	OTYSNK9Q	PGFRB_HUMAN	Decreases Expression	[13]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[13]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[11]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Expression	[13]
S-formylglutathione hydrolase (ESD)	OTUSIBPS	ESTD_HUMAN	Increases Expression	[11]
Elongation factor 2 (EEF2)	OTZ7SZ39	EF2_HUMAN	Increases Expression	[11]
Pyruvate kinase PKM (PKM)	OTLHHMC2	KPYM_HUMAN	Decreases Expression	[11]
Serine/threonine-protein kinase B-raf (BRAF)	OT7S81XQ	BRAF_HUMAN	Decreases Expression	[13]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Decreases Expression	[11]
Intron Large complex component GCFC2 (GCFC2)	OTC7FRXL	GCFC2_HUMAN	Increases Expression	[11]
Proteasome subunit alpha type-1 (PSMA1)	OTNBVM2U	PSA1_HUMAN	Increases Expression	[11]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Affects Phosphorylation	[13]
M-phase inducer phosphatase 3 (CDC25C)	OTPQI71S	MPIP3_HUMAN	Decreases Expression	[13]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[13]
Radixin (RDX)	OTNSYUN6	RADI_HUMAN	Increases Expression	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[13]
Serpin H1 (SERPINH1)	OTKGI7BS	SERPH_HUMAN	Decreases Expression	[11]
Small ubiquitin-related modifier 3 (SUMO3)	OTTUJQJ1	SUMO3_HUMAN	Decreases Expression	[11]
Peptidyl-prolyl cis-trans isomerase A (PPIA)	OTHJMWQQ	PPIA_HUMAN	Increases Expression	[11]
Echinoderm microtubule-associated protein-like 5 (EML5)	OT0EFCPB	EMAL5_HUMAN	Increases Expression	[11]
Interleukin enhancer-binding factor 3 (ILF3)	OTKMZ5K5	ILF3_HUMAN	Decreases Expression	[11]
Eukaryotic translation initiation factor 3 subunit I (EIF3I)	OTE07WND	EIF3I_HUMAN	Decreases Expression	[11]
3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10)	OT7RJON4	HCD2_HUMAN	Decreases Expression	[11]
Phenylalanine--tRNA ligase beta subunit (FARSB)	OT8N9TT5	SYFB_HUMAN	Increases Expression	[11]
Protein PALS2 (PALS2)	OTV12NKE	PALS2_HUMAN	Increases Expression	[11]
Cingulin (CGN)	OTBCQ8AQ	CING_HUMAN	Decreases Expression	[11]
Poly polymerase 2 (PARP2)	OTYL81ZI	PARP2_HUMAN	Increases Expression	[11]
Hypoxia up-regulated protein 1 (HYOU1)	OTBGBSOV	HYOU1_HUMAN	Decreases Expression	[11]
Phosphoserine aminotransferase (PSAT1)	OTVV1YV9	SERC_HUMAN	Increases Expression	[11]

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] Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
• [3] ClinicalTrials.gov (NCT01854034) Phase 2 Study of AUY922 in NSCLC Patients With Exon 20 Insertion Mutations in EGFR. U.S. National Institutes of Health.
• [4] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027019)
• [5] Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10931-6.
• [6] In vitro proguanil activation to cycloguanil is mediated by CYP2C19 and CYP3A4 in adult Chinese liver microsomes. Acta Pharmacol Sin. 2000 Aug;21(8):747-52.
• [7] Comparison of (S)-mephenytoin and proguanil oxidation in vitro: contribution of several CYP isoforms. Br J Clin Pharmacol. 1999 Aug;48(2):158-67.
• [8] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [9] Polymorphic oxidative metabolism of proguanil in a Nigerian population. Eur J Clin Pharmacol. 2002 Nov;58(8):543-5.
• [10] Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
• [11] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [12] Recent advances in Hsp90 inhibitors as antitumor agents. Anticancer Agents Med Chem. 2008 Oct;8(7):761-82.
• [13] Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma. Cancer. 2013 Jan 15;119(2):293-303. doi: 10.1002/cncr.27743. Epub 2012 Jul 18.