Details of the Drug Combination

General Information of Drug Combination (ID: DC2I1PQ)

• Drug Combination Name: MK-4827 + RTB101
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  MK-4827 (DMLYGH4): Small molecular drug
  RTB101 (DM62QTW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HT29
  Zero Interaction Potency (ZIP) Score: 9.81
  Bliss Independence Score: 9.29
  Loewe Additivity Score: 16.04
  LHighest Single Agent (HSA) Score: 17.25

Molecular Interaction Atlas of This Drug Combination

Indication(s) of MK-4827

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

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]

Indication(s) of RTB101

Disease Entry	ICD 11	Status	REF
Respiratory tract infection	CA45	Phase 3	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[5]

RTB101 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
CREB-regulated transcription coactivator 1 (TORC1)	TT4GO0F	CRTC1_HUMAN	Inhibitor	[10]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCD723T	ES2	Investigative	[11]
Breast and ovarian cancer syndrome	DCU6HS1	UWB1289	Investigative	[12]
Breast and ovarian cancer syndrome	DC84CA9	UWB1289+BRCA1	Investigative	[12]
Breast carcinoma	DCN7SGM	ZR751	Investigative	[12]
Breast carcinoma	DC87O78	KPL1	Investigative	[12]
Breast carcinoma	DCKIE1M	OCUBM	Investigative	[12]
Carcinoma	DCEELWL	OV90	Investigative	[12]
Carcinoma	DCZIJID	EFM192B	Investigative	[12]
Carcinoma	DC2MZW9	MDAMB436	Investigative	[12]
Colon adenocarcinoma	DCK01CR	LOVO	Investigative	[12]
Colon carcinoma	DCP62QP	RKO	Investigative	[12]
Invasive ductal carcinoma	DCM5A9G	T-47D	Investigative	[12]
Rectal adenocarcinoma	DC0MC7G	SW837	Investigative	[12]
Adenocarcinoma	DC73NTU	CAOV3	Investigative	[1]
Adenocarcinoma	DCRA69Y	OVCAR3	Investigative	[1]
Adenocarcinoma	DC41PDY	A427	Investigative	[1]
Adenocarcinoma	DCDD7TA	NCIH1650	Investigative	[1]
Adenocarcinoma	DCXJT2O	NCIH2122	Investigative	[1]
Adenocarcinoma	DCVSPSC	NCIH23	Investigative	[1]
Adenocarcinoma	DCFMSGR	NCIH520	Investigative	[1]
Adenocarcinoma	DCLO61D	COLO320DM	Investigative	[1]
Adenocarcinoma	DCP3DTI	DLD1	Investigative	[1]
Adenocarcinoma	DCGIHIB	HCT116	Investigative	[1]
Adenocarcinoma	DC0SQ46	SW-620	Investigative	[1]
Amelanotic melanoma	DCMIY7Q	A2058	Investigative	[1]
Germ cell tumour	DCE28IL	PA1	Investigative	[1]
Large cell lung carcinoma	DCC4HKB	NCI-H460	Investigative	[1]
Malignant melanoma	DC1SLZC	HT144	Investigative	[1]
Malignant melanoma	DC5ENSD	RPMI7951	Investigative	[1]
Malignant melanoma	DCVFPMO	SKMEL30	Investigative	[1]
Malignant melanoma	DCBT7KV	UACC62	Investigative	[1]
Malignant melanoma	DCDIM50	A375	Investigative	[1]
Mesothelioma	DCGNDWF	MSTO	Investigative	[1]
Non small cell carcinoma	DCTEKI5	SKMES1	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DCICY6D	A2780	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCBA8UJ	SK-OV-3	Investigative	[1]
Prostate carcinoma	DCMZVH6	LNCAP	Investigative	[1]
Prostate carcinoma	DCCKFAM	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 (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.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] ClinicalTrials.gov (NCT04139915) Effect of RTB101 on Illness Associated With Respiratory Tract Infections in the Elderly. U.S. National Institutes of Health.
• [5] ClinicalTrials.gov (NCT04409327) Phase 2 Study to Determine if RTB101 Reduces the Severity of COVID-19 in Older Adults Residing in Nursing Homes. U.S. National Institutes of Health.
• [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] Anti-ageing pipeline starts to mature.Nat Rev Drug Discov. 2018 Sep;17(9):609-612.
• [11] 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.
• [12] 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.