Details of the Drug Combination

General Information of Drug Combination (ID: DCMW68D)

• Drug Combination Name: NVP-AUY922 + Cantharidin
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  NVP-AUY922 (DMTYXQF): Small molecular drug
  Cantharidin (DMBP5N3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 47.493
  Bliss Independence Score: 44.765
  Loewe Additivity Score: 8.542
  LHighest Single Agent (HSA) Score: 19.782

Molecular Interaction Atlas of This Drug Combination

Indication(s) of NVP-AUY922

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

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	[6]

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	[5]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[7]
Fibroblast growth factor 1 (FGF1)	OT8I64X8	FGF1_HUMAN	Decreases Expression	[5]
ATP synthase subunit beta, mitochondrial (ATP5F1B)	OTLFZUQK	ATPB_HUMAN	Decreases Expression	[5]
Insulin-like growth factor 1 receptor (IGF1R)	OTXJIF13	IGF1R_HUMAN	Decreases Expression	[7]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Decreases Expression	[7]
Platelet-derived growth factor receptor beta (PDGFRB)	OTYSNK9Q	PGFRB_HUMAN	Decreases Expression	[7]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[7]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[5]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Expression	[7]
S-formylglutathione hydrolase (ESD)	OTUSIBPS	ESTD_HUMAN	Increases Expression	[5]
Elongation factor 2 (EEF2)	OTZ7SZ39	EF2_HUMAN	Increases Expression	[5]
Pyruvate kinase PKM (PKM)	OTLHHMC2	KPYM_HUMAN	Decreases Expression	[5]
Serine/threonine-protein kinase B-raf (BRAF)	OT7S81XQ	BRAF_HUMAN	Decreases Expression	[7]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Decreases Expression	[5]
Intron Large complex component GCFC2 (GCFC2)	OTC7FRXL	GCFC2_HUMAN	Increases Expression	[5]
Proteasome subunit alpha type-1 (PSMA1)	OTNBVM2U	PSA1_HUMAN	Increases Expression	[5]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Affects Phosphorylation	[7]
M-phase inducer phosphatase 3 (CDC25C)	OTPQI71S	MPIP3_HUMAN	Decreases Expression	[7]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[7]
Radixin (RDX)	OTNSYUN6	RADI_HUMAN	Increases Expression	[5]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[7]
Serpin H1 (SERPINH1)	OTKGI7BS	SERPH_HUMAN	Decreases Expression	[5]
Small ubiquitin-related modifier 3 (SUMO3)	OTTUJQJ1	SUMO3_HUMAN	Decreases Expression	[5]
Peptidyl-prolyl cis-trans isomerase A (PPIA)	OTHJMWQQ	PPIA_HUMAN	Increases Expression	[5]
Echinoderm microtubule-associated protein-like 5 (EML5)	OT0EFCPB	EMAL5_HUMAN	Increases Expression	[5]
Interleukin enhancer-binding factor 3 (ILF3)	OTKMZ5K5	ILF3_HUMAN	Decreases Expression	[5]
Eukaryotic translation initiation factor 3 subunit I (EIF3I)	OTE07WND	EIF3I_HUMAN	Decreases Expression	[5]
3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10)	OT7RJON4	HCD2_HUMAN	Decreases Expression	[5]
Phenylalanine--tRNA ligase beta subunit (FARSB)	OT8N9TT5	SYFB_HUMAN	Increases Expression	[5]
Protein PALS2 (PALS2)	OTV12NKE	PALS2_HUMAN	Increases Expression	[5]
Cingulin (CGN)	OTBCQ8AQ	CING_HUMAN	Decreases Expression	[5]
Poly polymerase 2 (PARP2)	OTYL81ZI	PARP2_HUMAN	Increases Expression	[5]
Hypoxia up-regulated protein 1 (HYOU1)	OTBGBSOV	HYOU1_HUMAN	Decreases Expression	[5]
Phosphoserine aminotransferase (PSAT1)	OTVV1YV9	SERC_HUMAN	Increases Expression	[5]

Indication(s) of Cantharidin

Disease Entry	ICD 11	Status	REF
Molluscum contagiosum infection	1E76	Approved	[4]

Cantharidin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine PP1-alpha (PPP1CA)	TTFLH0E	PP1A_HUMAN	Inhibitor	[9]

Cantharidin Interacts with 45 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[10]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Increases Expression	[10]
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Increases Expression	[8]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Decreases Expression	[11]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[8]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[12]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[8]
Sphingosine 1-phosphate receptor 2 (S1PR2)	OTRTJF29	S1PR2_HUMAN	Increases Expression	[11]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Increases Expression	[13]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Expression	[13]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[8]
Calpain-1 catalytic subunit (CAPN1)	OTK6OQZR	CAN1_HUMAN	Increases Expression	[8]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[14]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[8]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[12]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[8]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Increases Expression	[14]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[14]
Calpain-2 catalytic subunit (CAPN2)	OTIAPE5J	CAN2_HUMAN	Increases Expression	[8]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[13]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Increases Cleavage	[8]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Affects Expression	[11]
DNA cytosine-5)-methyltransferase 1 (DNMT1)	OTM2DGTK	DNMT1_HUMAN	Decreases Expression	[11]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[8]
Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1)	OT5BZ1J9	P85A_HUMAN	Decreases Expression	[14]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[8]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Affects Expression	[11]
Nitric oxide synthase 1 (NOS1)	OT7M8XVG	NOS1_HUMAN	Decreases Expression	[11]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[8]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[8]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Decreases Expression	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[15]
Cyclin-dependent kinase 4 inhibitor B (CDKN2B)	OTAG24N1	CDN2B_HUMAN	Affects Expression	[14]
Caspase-4 (CASP4)	OTVQTV1L	CASP4_HUMAN	Increases Expression	[8]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Expression	[8]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Expression	[8]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[14]
Hepcidin (HAMP)	OT607RBL	HEPC_HUMAN	Decreases Expression	[16]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Decreases Expression	[8]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Decreases Expression	[14]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[12]
Endonuclease G, mitochondrial (ENDOG)	OT5IM7B3	NUCG_HUMAN	Increases Expression	[8]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Increases Expression	[13]
Ubiquitin-like-conjugating enzyme ATG3 (ATG3)	OT28VBVK	ATG3_HUMAN	Increases Expression	[13]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Expression	[13]

References

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• [2] ClinicalTrials.gov (NCT01854034) Phase 2 Study of AUY922 in NSCLC Patients With Exon 20 Insertion Mutations in EGFR. U.S. National Institutes of Health.
• [3] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027019)
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] 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.
• [6] Recent advances in Hsp90 inhibitors as antitumor agents. Anticancer Agents Med Chem. 2008 Oct;8(7):761-82.
• [7] 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.
• [8] Anticancer effects of cantharidin in A431 human skin cancer (Epidermoid carcinoma) cells in vitro and in vivo. Environ Toxicol. 2017 Mar;32(3):723-738. doi: 10.1002/tox.22273. Epub 2016 Apr 25.
• [9] Serine-threonine protein phosphatase inhibitors: development of potential therapeutic strategies. J Med Chem. 2002 Mar 14;45(6):1151-75.
• [10] Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ Health Perspect. 2003 Dec;111(16):1877-82.
• [11] Hepatoxicity mechanism of cantharidin-induced liver LO2 cells by LC-MS metabolomics combined traditional approaches. Toxicol Lett. 2020 Oct 15;333:49-61. doi: 10.1016/j.toxlet.2020.07.024. Epub 2020 Jul 26.
• [12] [Apoptosis induced by cantharidin in human pulmonary carcinoma cells A549 and its molecular mechanisms]. Zhonghua Zhong Liu Za Zhi. 2005 Jun;27(6):330-4.
• [13] Endoplasmic reticulum stress contributes to autophagy and apoptosis in cantharidin-induced nephrotoxicity. Food Chem Toxicol. 2022 May;163:112986. doi: 10.1016/j.fct.2022.112986. Epub 2022 Apr 6.
• [14] Cantharidin suppresses gastric cancer cell migration/invasion by inhibiting the PI3K/Akt signaling pathway via CCAT1. Chem Biol Interact. 2020 Feb 1;317:108939. doi: 10.1016/j.cbi.2020.108939. Epub 2020 Jan 13.
• [15] Analysis of cantharidin-induced nephrotoxicity in HK-2 cells using untargeted metabolomics and an integrative network pharmacology analysis. Food Chem Toxicol. 2020 Dec;146:111845. doi: 10.1016/j.fct.2020.111845. Epub 2020 Nov 2.
• [16] A HAMP promoter bioassay system for identifying chemical compounds that modulate hepcidin expression. Exp Hematol. 2015 May;43(5):404-413.e5. doi: 10.1016/j.exphem.2015.01.005. Epub 2015 Jan 26.