Details of the Drug Combination

General Information of Drug Combination (ID: DCBWQD3)

• Drug Combination Name: MK-2206 + MK-4827
• Indication: Invasive ductal carcinoma; Status: Investigative [1]
• Component Drugs:
  MK-2206 (DMT1OZ6): Small molecular drug
  MK-4827 (DMLYGH4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T-47D
  Zero Interaction Potency (ZIP) Score: 4.29
  Bliss Independence Score: 2.74
  Loewe Additivity Score: 9.18
  LHighest Single Agent (HSA) Score: 10.19

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 MK-4827

Disease Entry	ICD 11	Status	REF
Ovarian cancer	2C73	Phase 3	[4]
Breast cancer	2C60-2C65	Phase 2	[5]
Ewing sarcoma	2B52	Phase 1	[5]

MK-4827 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Poly [ADP-ribose] polymerase (PARP)	TTEBCY8	NOUNIPROTAC	Modulator	[14]

MK-4827 Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[15]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[16]
Beta-glucuronidase (GUSB)	DEP54UE	BGLR_HUMAN	Metabolism	[16]

MK-4827 Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCSSUSV	CAOV3	Investigative	[18]
Adenocarcinoma	DC6NTIW	OVCAR3	Investigative	[18]
Adenocarcinoma	DCUOUSC	A427	Investigative	[18]
Adenocarcinoma	DCTX7DZ	NCIH1650	Investigative	[18]
Adenocarcinoma	DCXZNOK	NCIH2122	Investigative	[18]
Adenocarcinoma	DCRZWRC	NCIH23	Investigative	[18]
Adenocarcinoma	DCFLUKF	NCIH520	Investigative	[18]
Adenocarcinoma	DCQ5930	COLO320DM	Investigative	[18]
Adenocarcinoma	DC56Y63	DLD1	Investigative	[18]
Adenocarcinoma	DCLRUJV	HCT116	Investigative	[18]
Adenocarcinoma	DC4V7D6	HT29	Investigative	[18]
Adenocarcinoma	DC6PSOL	SW-620	Investigative	[18]
Amelanotic melanoma	DCLKM9B	A2058	Investigative	[18]
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCLU5O8	ES2	Investigative	[18]
Germ cell tumour	DC0E0CB	PA1	Investigative	[18]
Large cell lung carcinoma	DCMJ6NE	NCI-H460	Investigative	[18]
Malignant melanoma	DCVFCWU	A375	Investigative	[18]
Malignant melanoma	DC9IDR0	HT144	Investigative	[18]
Malignant melanoma	DCB7NCC	RPMI7951	Investigative	[18]
Malignant melanoma	DCSPTQ5	SKMEL30	Investigative	[18]
Malignant melanoma	DC9FVKQ	UACC62	Investigative	[18]
Mesothelioma	DCGZD4Z	MSTO	Investigative	[18]
Non small cell carcinoma	DCJBWKJ	SKMES1	Investigative	[18]
Ovarian endometrioid adenocarcinoma	DC26H0N	A2780	Investigative	[18]
Ovarian serous cystadenocarcinoma	DC41BAX	SK-OV-3	Investigative	[18]
Prostate carcinoma	DC2RD92	LNCAP	Investigative	[18]
Prostate carcinoma	DCN3MHL	VCAP	Investigative	[18]
Breast and ovarian cancer syndrome	DCFG80X	UWB1289	Investigative	[1]
Breast carcinoma	DCPS202	KPL1	Investigative	[1]
Breast carcinoma	DCADZ15	OCUBM	Investigative	[1]
Carcinoma	DCY2WT1	OV90	Investigative	[1]
Carcinoma	DCEQC76	EFM192B	Investigative	[1]
Carcinoma	DCGHF2G	MDAMB436	Investigative	[1]
Colon adenocarcinoma	DCA6YBG	LOVO	Investigative	[1]
Colon carcinoma	DCFLCNU	RKO	Investigative	[1]

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 (NCT03602859) A Phase 3 Comparison of Platinum-based Therapy With TSR-042 and Niraparib Versus Standard of Care (SOC) Platinum-based Therapy as First-line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST). U.S. National Institutes of Health.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
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• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [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] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [15] Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85.
• [16] Summary of FDA-approved anticancer cytotoxic drugs at May 2019.
• [17] Autophagy up-regulated by MEK/ERK promotes the repair of DNA damage caused by aflatoxin B1. Toxicol Mech Methods. 2022 Feb;32(2):87-96. doi: 10.1080/15376516.2021.1968985. Epub 2021 Aug 26.
• [18] 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.