Details of the Drug Combination

General Information of Drug Combination (ID: DCCZCVB)

• Drug Combination Name: MK-2206 + NVP-AUY922
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  MK-2206 (DMT1OZ6): Small molecular drug
  NVP-AUY922 (DMTYXQF): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 5.86
  Bliss Independence Score: 6.25
  Loewe Additivity Score: 0.253
  LHighest Single Agent (HSA) Score: 4.191

Molecular Interaction Atlas of This Drug Combination

Indication(s) of MK-2206

Disease Entry	ICD 11	Status	REF
Rectal adenocarcinoma	2B92	Phase 2	[2]
Nasopharyngeal carcinoma	2B6B	Investigative	[3]

MK-2206 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
RAC-gamma serine/threonine-protein kinase (AKT3)	TTAZ05C	AKT3_HUMAN	Modulator	[7]
E2 ubiquitin-conjugating enzyme T (UBE2T)	TT0A1R8	UBE2T_HUMAN	Inhibitor	[3]

MK-2206 Interacts with 20 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Expression	[8]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[6]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Increases Expression	[8]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[6]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Expression	[6]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[9]
Vascular endothelial growth factor receptor 1 (FLT1)	OTT0OGYS	VGFR1_HUMAN	Decreases Expression	[6]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[6]
Endothelin receptor type B (EDNRB)	OTLLZV3P	EDNRB_HUMAN	Increases Expression	[6]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Affects Response To Substance	[10]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[11]
T-lymphocyte activation antigen CD80 (CD80)	OTJBLUQE	CD80_HUMAN	Decreases Expression	[6]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[6]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[11]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[6]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[12]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[11]
Interferon regulatory factor 8 (IRF8)	OT8YSNI4	IRF8_HUMAN	Decreases Expression	[6]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[11]
Proline-rich AKT1 substrate 1 (AKT1S1)	OT4JHN4Y	AKTS1_HUMAN	Decreases Phosphorylation	[13]

Indication(s) of NVP-AUY922

Disease Entry	ICD 11	Status	REF
Multiple myeloma	2A83	Phase 2	[4]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[5]

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	[15]

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	[14]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[16]
Fibroblast growth factor 1 (FGF1)	OT8I64X8	FGF1_HUMAN	Decreases Expression	[14]
ATP synthase subunit beta, mitochondrial (ATP5F1B)	OTLFZUQK	ATPB_HUMAN	Decreases Expression	[14]
Insulin-like growth factor 1 receptor (IGF1R)	OTXJIF13	IGF1R_HUMAN	Decreases Expression	[16]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Decreases Expression	[16]
Platelet-derived growth factor receptor beta (PDGFRB)	OTYSNK9Q	PGFRB_HUMAN	Decreases Expression	[16]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[16]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[14]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Expression	[16]
S-formylglutathione hydrolase (ESD)	OTUSIBPS	ESTD_HUMAN	Increases Expression	[14]
Elongation factor 2 (EEF2)	OTZ7SZ39	EF2_HUMAN	Increases Expression	[14]
Pyruvate kinase PKM (PKM)	OTLHHMC2	KPYM_HUMAN	Decreases Expression	[14]
Serine/threonine-protein kinase B-raf (BRAF)	OT7S81XQ	BRAF_HUMAN	Decreases Expression	[16]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Decreases Expression	[14]
Intron Large complex component GCFC2 (GCFC2)	OTC7FRXL	GCFC2_HUMAN	Increases Expression	[14]
Proteasome subunit alpha type-1 (PSMA1)	OTNBVM2U	PSA1_HUMAN	Increases Expression	[14]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Affects Phosphorylation	[16]
M-phase inducer phosphatase 3 (CDC25C)	OTPQI71S	MPIP3_HUMAN	Decreases Expression	[16]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[16]
Radixin (RDX)	OTNSYUN6	RADI_HUMAN	Increases Expression	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[16]
Serpin H1 (SERPINH1)	OTKGI7BS	SERPH_HUMAN	Decreases Expression	[14]
Small ubiquitin-related modifier 3 (SUMO3)	OTTUJQJ1	SUMO3_HUMAN	Decreases Expression	[14]
Peptidyl-prolyl cis-trans isomerase A (PPIA)	OTHJMWQQ	PPIA_HUMAN	Increases Expression	[14]
Echinoderm microtubule-associated protein-like 5 (EML5)	OT0EFCPB	EMAL5_HUMAN	Increases Expression	[14]
Interleukin enhancer-binding factor 3 (ILF3)	OTKMZ5K5	ILF3_HUMAN	Decreases Expression	[14]
Eukaryotic translation initiation factor 3 subunit I (EIF3I)	OTE07WND	EIF3I_HUMAN	Decreases Expression	[14]
3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10)	OT7RJON4	HCD2_HUMAN	Decreases Expression	[14]
Phenylalanine--tRNA ligase beta subunit (FARSB)	OT8N9TT5	SYFB_HUMAN	Increases Expression	[14]
Protein PALS2 (PALS2)	OTV12NKE	PALS2_HUMAN	Increases Expression	[14]
Cingulin (CGN)	OTBCQ8AQ	CING_HUMAN	Decreases Expression	[14]
Poly polymerase 2 (PARP2)	OTYL81ZI	PARP2_HUMAN	Increases Expression	[14]
Hypoxia up-regulated protein 1 (HYOU1)	OTBGBSOV	HYOU1_HUMAN	Decreases Expression	[14]
Phosphoserine aminotransferase (PSAT1)	OTVV1YV9	SERC_HUMAN	Increases Expression	[14]

References

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• [2] 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: 7945).
• [3] UBE2T promotes nasopharyngeal carcinoma cell proliferation, invasion, and metastasis by activating the AKT/GSK3/-catenin pathway.Oncotarget. 2016 Mar 22;7(12):15161-72.
• [4] ClinicalTrials.gov (NCT01854034) Phase 2 Study of AUY922 in NSCLC Patients With Exon 20 Insertion Mutations in EGFR. U.S. National Institutes of Health.
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• [12] -Mangostin alleviates liver fibrosis through Sirtuin 3-superoxide-high mobility group box 1 signaling axis. Toxicol Appl Pharmacol. 2019 Jan 15;363:142-153. doi: 10.1016/j.taap.2018.11.011. Epub 2018 Nov 29.
• [13] Akt activation by Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in ovarian cancer cells. J Biol Chem. 2017 Aug 25;292(34):14188-14204. doi: 10.1074/jbc.M117.778464. Epub 2017 Jun 20.
• [14] 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.
• [15] Recent advances in Hsp90 inhibitors as antitumor agents. Anticancer Agents Med Chem. 2008 Oct;8(7):761-82.
• [16] 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.