Details of the Drug Combination

General Information of Drug Combination (ID: DCY9QLV)

• Drug Combination Name: MK-1775 + MK-2206
• Indication: Invasive ductal carcinoma; Status: Investigative [1]
• Component Drugs:
  MK-1775 (DM3WDZ5): Small molecular drug
  MK-2206 (DMT1OZ6): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T-47D
  Zero Interaction Potency (ZIP) Score: 6.62
  Bliss Independence Score: 7.25
  Loewe Additivity Score: 13.25
  LHighest Single Agent (HSA) Score: 14.23

Molecular Interaction Atlas of This Drug Combination

Indication(s) of MK-1775

Disease Entry	ICD 11	Status	REF
Ovarian cancer	2C73	Phase 2	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]

MK-1775 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Wee1-like protein kinase (WEE1)	TTJFOAL	WEE1_HUMAN	Inhibitor	[7]

MK-1775 Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Phosphorylation	[6]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Response To Substance	[6]

Indication(s) of MK-2206

Disease Entry	ICD 11	Status	REF
Rectal adenocarcinoma	2B92	Phase 2	[4]
Nasopharyngeal carcinoma	2B6B	Investigative	[5]

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	[9]
E2 ubiquitin-conjugating enzyme T (UBE2T)	TT0A1R8	UBE2T_HUMAN	Inhibitor	[5]

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	[10]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[8]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Increases Expression	[10]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[8]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Expression	[8]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[11]
Vascular endothelial growth factor receptor 1 (FLT1)	OTT0OGYS	VGFR1_HUMAN	Decreases Expression	[8]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[8]
Endothelin receptor type B (EDNRB)	OTLLZV3P	EDNRB_HUMAN	Increases Expression	[8]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Affects Response To Substance	[12]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[13]
T-lymphocyte activation antigen CD80 (CD80)	OTJBLUQE	CD80_HUMAN	Decreases Expression	[8]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[13]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[8]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[14]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[13]
Interferon regulatory factor 8 (IRF8)	OT8YSNI4	IRF8_HUMAN	Decreases Expression	[8]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[13]
Proline-rich AKT1 substrate 1 (AKT1S1)	OT4JHN4Y	AKTS1_HUMAN	Decreases Phosphorylation	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCFC43W	CAOV3	Investigative	[16]
Adenocarcinoma	DCCO6X0	A427	Investigative	[16]
Adenocarcinoma	DC7JPOQ	NCIH2122	Investigative	[16]
Adenocarcinoma	DCPF5PE	NCIH23	Investigative	[16]
Adenocarcinoma	DC369HV	NCIH520	Investigative	[16]
Adenocarcinoma	DC52IWZ	COLO320DM	Investigative	[16]
Adenocarcinoma	DCQHCN2	HCT116	Investigative	[16]
Adenocarcinoma	DCQJKT4	HT29	Investigative	[16]
Adenocarcinoma	DCYS0LN	SW-620	Investigative	[16]
Amelanotic melanoma	DCPZ8QH	A2058	Investigative	[16]
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DC3JZJ4	ES2	Investigative	[16]
Germ cell tumour	DC3R8WO	PA1	Investigative	[16]
Large cell lung carcinoma	DCB8UL3	NCI-H460	Investigative	[16]
Malignant melanoma	DCXGS5G	A375	Investigative	[16]
Malignant melanoma	DCI0AK7	RPMI7951	Investigative	[16]
Malignant melanoma	DCAUF9J	SKMEL30	Investigative	[16]
Malignant melanoma	DCOP21X	UACC62	Investigative	[16]
Non small cell carcinoma	DCK8X1R	SKMES1	Investigative	[16]
Ovarian endometrioid adenocarcinoma	DCDJCT3	A2780	Investigative	[16]
Prostate carcinoma	DC9S7QC	VCAP	Investigative	[16]
Breast and ovarian cancer syndrome	DCHT9J8	UWB1289	Investigative	[1]
Breast carcinoma	DC2MXPD	KPL1	Investigative	[1]
Breast carcinoma	DCCFBFL	OCUBM	Investigative	[1]
Carcinoma	DCIIOM2	MDAMB436	Investigative	[1]
Colon carcinoma	DCQ1TMN	RKO	Investigative	[1]
Rectal adenocarcinoma	DCQ8DJH	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: 7702).
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 7945).
• [5] UBE2T promotes nasopharyngeal carcinoma cell proliferation, invasion, and metastasis by activating the AKT/GSK3/-catenin pathway.Oncotarget. 2016 Mar 22;7(12):15161-72.
• [6] Functional kinomics identifies candidate therapeutic targets in head and neck cancer. Clin Cancer Res. 2014 Aug 15;20(16):4274-88. doi: 10.1158/1078-0432.CCR-13-2858.
• [7] A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] -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.
• [15] 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.
• [16] 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.