Details of the Drug Combination

General Information of Drug Combination (ID: DC0CH6X)

• Drug Combination Name: Everolimus + NVP-AUY922
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  Everolimus (DM8X2EH): Small molecular drug
  NVP-AUY922 (DMTYXQF): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 15.634
  Bliss Independence Score: 13.187
  Loewe Additivity Score: 3.05
  LHighest Single Agent (HSA) Score: 5.101

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Everolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Advanced/metastatic breast cancer	2C60	Approved	[3]
Brainstem neoplasm	N.A.	Approved	[2]
Breast carcinoma	N.A.	Approved	[2]
Graft-versus-host disease	4B24	Approved	[2]
Intracranial meningioma	N.A.	Approved	[2]
Leukemia	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Mucosal melanoma	N.A.	Approved	[2]
Multiple sclerosis	8A40	Approved	[2]
Plasma cell myeloma	2A83.1	Approved	[2]
Prostate cancer	2C82.0	Approved	[2]
Renal cell carcinoma	2C90	Approved	[4]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Tuberous sclerosis	LD2D.2	Approved	[2]
Kidney cancer	2C90.0	Phase 3	[4]
Castration-resistant prostate carcinoma	N.A.	Investigative	[2]
Colon cancer	2B90.Z	Investigative	[2]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[5]
Neuroblastoma	2D11.2	Investigative	[2]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[2]
Polycystic kidney disease	GB8Y	Investigative	[2]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[5]

Everolimus Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[8]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[5]

Everolimus Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Everolimus Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]

Indication(s) of NVP-AUY922

Disease Entry	ICD 11	Status	REF
Multiple myeloma	2A83	Phase 2	[6]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[7]

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] Everolimus FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 5889).
• [5] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [6] ClinicalTrials.gov (NCT01854034) Phase 2 Study of AUY922 in NSCLC Patients With Exon 20 Insertion Mutations in EGFR. U.S. National Institutes of Health.
• [7] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027019)
• [8] Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma. Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9.
• [9] Closer to the Site of Action: Everolimus Concentrations in Peripheral Blood Mononuclear Cells Correlate Well With Whole Blood Concentrations. Ther Drug Monit. 2015 Oct;37(5):675-80.
• [10] The evolving experience using everolimus in clinical transplantation. Transplant Proc. 2004 Mar;36(2 Suppl):495S-499S.
• [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.