Details of the Drug Combination

General Information of Drug Combination (ID: DCE21DR)

• Drug Combination Name: MK-5108 + MK-4827
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  MK-5108 (DMFGYKS): Small molecular drug
  MK-4827 (DMLYGH4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HCT116
  Zero Interaction Potency (ZIP) Score: 3.34
  Bliss Independence Score: 1.85
  Loewe Additivity Score: 2.29
  LHighest Single Agent (HSA) Score: 2.17

Molecular Interaction Atlas of This Drug Combination

Indication(s) of MK-5108

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

MK-5108 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aurora kinase B (AURKB)	TT5LS6T	AURKB_HUMAN	Inhibitor	[5]
Aurora kinase A (AURKA)	TTPS3C0	AURKA_HUMAN	Inhibitor	[5]

Indication(s) of MK-4827

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

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	[6]

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	[7]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[8]
Beta-glucuronidase (GUSB)	DEP54UE	BGLR_HUMAN	Metabolism	[8]

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	[9]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast and ovarian cancer syndrome	DCBGGSO	UWB1289+BRCA1	Investigative	[10]
Breast carcinoma	DC22EC6	KPL1	Investigative	[10]
Breast carcinoma	DCOJGWP	OCUBM	Investigative	[10]
Carcinoma	DCSQ5YL	EFM192B	Investigative	[10]
Colon carcinoma	DCLKJ8Q	RKO	Investigative	[10]
Invasive ductal carcinoma	DCDIC8Q	T-47D	Investigative	[10]
Rectal adenocarcinoma	DC30C6P	SW837	Investigative	[10]
Adenocarcinoma	DC5W0QB	CAOV3	Investigative	[1]
Adenocarcinoma	DCPONMC	OVCAR3	Investigative	[1]
Adenocarcinoma	DCR8G24	A427	Investigative	[1]
Adenocarcinoma	DCO2W8T	NCIH2122	Investigative	[1]
Adenocarcinoma	DCNYE0W	NCIH520	Investigative	[1]
Adenocarcinoma	DCOTPP6	COLO320DM	Investigative	[1]
Adenocarcinoma	DCGZ7WH	DLD1	Investigative	[1]
Adenocarcinoma	DCT21UE	HT29	Investigative	[1]
Adenocarcinoma	DCC3F5K	SW-620	Investigative	[1]
Amelanotic melanoma	DC0XA7R	A2058	Investigative	[1]
Malignant melanoma	DCQO4VA	A375	Investigative	[1]
Malignant melanoma	DC2QYN9	RPMI7951	Investigative	[1]
Malignant melanoma	DCND5UR	SKMEL30	Investigative	[1]
Mesothelioma	DCXDZ90	MSTO	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DCTRTM1	A2780	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCKW65Q	SK-OV-3	Investigative	[1]
Prostate carcinoma	DCFEYQ1	VCAP	Investigative	[1]

References

• [1] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
• [2] ClinicalTrials.gov (NCT00543387) Treatment of Participants With Advanced and/or Refractory Solid Tumors (MK-5108-001 AM4). U.S. National Institutes of Health.
• [3] 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.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] 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.
• [6] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [7] 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.
• [8] Summary of FDA-approved anticancer cytotoxic drugs at May 2019.
• [9] 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.
• [10] 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.