Details of the Drug Combination

General Information of Drug Combination (ID: DCFXQ0T)

• Drug Combination Name: MK-2206 + SNX-2112
• Indication: Invasive ductal carcinoma; Status: Investigative [1]
• Component Drugs:
  MK-2206 (DMT1OZ6): Small molecular drug
  SNX-2112 (DMB5A80): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T-47D
  Zero Interaction Potency (ZIP) Score: 1.96
  Bliss Independence Score: 4.39
  Loewe Additivity Score: 0.15
  LHighest Single Agent (HSA) Score: 5.9

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	[6]
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	[7]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[5]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Increases Expression	[7]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[5]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Expression	[5]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[8]
Vascular endothelial growth factor receptor 1 (FLT1)	OTT0OGYS	VGFR1_HUMAN	Decreases Expression	[5]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[5]
Endothelin receptor type B (EDNRB)	OTLLZV3P	EDNRB_HUMAN	Increases Expression	[5]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Affects Response To Substance	[9]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[10]
T-lymphocyte activation antigen CD80 (CD80)	OTJBLUQE	CD80_HUMAN	Decreases Expression	[5]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[5]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[10]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[5]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[11]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[10]
Interferon regulatory factor 8 (IRF8)	OT8YSNI4	IRF8_HUMAN	Decreases Expression	[5]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[10]
Proline-rich AKT1 substrate 1 (AKT1S1)	OT4JHN4Y	AKTS1_HUMAN	Decreases Phosphorylation	[12]

Indication(s) of SNX-2112

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[4]

SNX-2112 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	[4]

SNX-2112 Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Inhibitor of nuclear factor kappa-B kinase subunit alpha (CHUK)	OTLF4ZB1	IKKA_HUMAN	Decreases Expression	[13]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[13]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[13]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Decreases Expression	[13]
Endoplasmin (HSP90B1)	OT02XLBR	ENPL_HUMAN	Decreases Expression	[13]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[13]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Expression	[13]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[13]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[13]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[13]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[13]
Heat shock protein 75 kDa, mitochondrial (TRAP1)	OTNG0L8J	TRAP1_HUMAN	Decreases Expression	[13]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[13]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCBFQUR	CAOV3	Investigative	[14]
Adenocarcinoma	DCWV1D9	A427	Investigative	[14]
Adenocarcinoma	DCCSU4U	NCIH1650	Investigative	[14]
Adenocarcinoma	DCB0W6J	NCIH2122	Investigative	[14]
Adenocarcinoma	DCDROV8	DLD1	Investigative	[14]
Adenocarcinoma	DCDNV8F	HT29	Investigative	[14]
Amelanotic melanoma	DCF7SL7	A2058	Investigative	[14]
Large cell lung carcinoma	DCI40S4	NCI-H460	Investigative	[14]
Malignant melanoma	DC5KAPJ	SKMEL30	Investigative	[14]
Malignant melanoma	DCQP548	UACC62	Investigative	[14]
Mesothelioma	DCJXBVU	MSTO	Investigative	[14]
Non small cell carcinoma	DC2D8NG	SKMES1	Investigative	[14]
Ovarian endometrioid adenocarcinoma	DC0ORDL	A2780	Investigative	[14]
Ovarian serous cystadenocarcinoma	DCJMKX8	SK-OV-3	Investigative	[14]
Prostate carcinoma	DCNRH0O	LNCAP	Investigative	[14]
Breast and ovarian cancer syndrome	DCW1X9R	UWB1289	Investigative	[1]
Breast and ovarian cancer syndrome	DCWB37O	UWB1289+BRCA1	Investigative	[1]
Carcinoma	DC9350T	MDAMB436	Investigative	[1]
Rectal adenocarcinoma	DC2LTA6	SW837	Investigative	[1]

References

• [1] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.
• [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] Heat shock protein 90: inhibitors in clinical trials. J Med Chem. 2010 Jan 14;53(1):3-17.
• [5] Chemerin promotes the pathogenesis of preeclampsia by activating CMKLR1/p-Akt/CEBP axis and inducing M1 macrophage polarization. Cell Biol Toxicol. 2022 Aug;38(4):611-628. doi: 10.1007/s10565-021-09636-7. Epub 2021 Aug 16.
• [6] First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors.J Clin Oncol.2011 Dec 10;29(35):4688-95.
• [7] Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells. Sci Rep. 2016 Nov 29;6:37997. doi: 10.1038/srep37997.
• [8] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
• [9] PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury. Toxicol Appl Pharmacol. 2019 Oct 15;381:114729. doi: 10.1016/j.taap.2019.114729. Epub 2019 Aug 22.
• [10] Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: eliminating activity by targeting at different levels. Oncotarget. 2012 Aug;3(8):811-23. doi: 10.18632/oncotarget.579.
• [11] -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.
• [12] 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.
• [13] The Hsp90 inhibitor SNX-2112, induces apoptosis in multidrug resistant K562/ADR cells through suppression of Akt/NF-B and disruption of mitochondria-dependent pathways. Chem Biol Interact. 2013 Sep 5;205(1):1-10. doi: 10.1016/j.cbi.2013.06.007. Epub 2013 Jun 15.
• [14] 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.