Details of the Drug Combination

General Information of Drug Combination (ID: DCR4NH7)

• Drug Combination Name: MK-1775 + 10-hydroxycamptothecin
• Indication: Breast carcinoma; Status: Investigative [1]
• Component Drugs:
  MK-1775 (DM3WDZ5): Small molecular drug
  10-hydroxycamptothecin (DM9WLN4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KPL1
  Zero Interaction Potency (ZIP) Score: 0.17
  Bliss Independence Score: 2.46
  Loewe Additivity Score: 8.06
  LHighest Single Agent (HSA) Score: 9.55

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	[6]

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	[5]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Response To Substance	[5]

Indication(s) of 10-hydroxycamptothecin

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

10-hydroxycamptothecin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase I (TOP1)	TTGTQHC	TOP1_HUMAN	Inhibitor	[4]

10-hydroxycamptothecin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[7]

10-hydroxycamptothecin Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Response To Substance	[8]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Affects Response To Substance	[9]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Response To Substance	[8]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCYAV9W	CAOV3	Investigative	[10]
Adenocarcinoma	DCKJVC3	A427	Investigative	[10]
Adenocarcinoma	DCJU6CE	NCIH1650	Investigative	[10]
Adenocarcinoma	DCSFCWT	NCIH2122	Investigative	[10]
Adenocarcinoma	DCT3STD	NCIH23	Investigative	[10]
Adenocarcinoma	DCTACFW	NCIH520	Investigative	[10]
Adenocarcinoma	DCFHGLW	COLO320DM	Investigative	[10]
Adenocarcinoma	DCE8N91	DLD1	Investigative	[10]
Adenocarcinoma	DCLYDCN	HCT116	Investigative	[10]
Adenocarcinoma	DCNBFSS	HT29	Investigative	[10]
Adenocarcinoma	DCMYNM0	SW-620	Investigative	[10]
Amelanotic melanoma	DCRBVT9	A2058	Investigative	[10]
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DC7JN0B	ES2	Investigative	[10]
Germ cell tumour	DCBUPKM	PA1	Investigative	[10]
Malignant melanoma	DCXOCQE	A375	Investigative	[10]
Malignant melanoma	DCOX20A	HT144	Investigative	[10]
Malignant melanoma	DCUFHTV	RPMI7951	Investigative	[10]
Malignant melanoma	DCL12RU	SKMEL30	Investigative	[10]
Malignant melanoma	DC7WTA4	UACC62	Investigative	[10]
Mesothelioma	DC7F29S	MSTO	Investigative	[10]
Non small cell carcinoma	DCRANYM	SKMES1	Investigative	[10]
Ovarian endometrioid adenocarcinoma	DCIPYX0	A2780	Investigative	[10]
Ovarian serous cystadenocarcinoma	DCE7JZD	SK-OV-3	Investigative	[10]
Prostate carcinoma	DCS1873	LNCAP	Investigative	[10]
Prostate carcinoma	DCW7VLR	VCAP	Investigative	[10]
Breast and ovarian cancer syndrome	DCAIH7B	UWB1289+BRCA1	Investigative	[1]
Breast carcinoma	DCQITCE	ZR751	Investigative	[1]
Breast carcinoma	DCEVLLZ	OCUBM	Investigative	[1]
Carcinoma	DCD287V	OV90	Investigative	[1]
Carcinoma	DCLK4KW	EFM192B	Investigative	[1]
Colon adenocarcinoma	DCY5C8B	LOVO	Investigative	[1]
Colon carcinoma	DC0R11T	RKO	Investigative	[1]
Invasive ductal carcinoma	DCZOGE0	T-47D	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] Upregulation of p21WAF1/CIP1 in human breast cancer cell lines MCF-7 and MDA-MB-468 undergoing apoptosis induced by natural product anticancer drugs 10-hydroxycamptothecin and camptothecin through p53-dependent and independent pathways. Int J Oncol. 1998 Apr;12(4):793-804.
• [5] 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.
• [6] 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.
• [7] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [8] siRNA-mediated Bcl-2 and Bcl-xl gene silencing sensitizes human hepatoblastoma cells to chemotherapeutic drugs. Clin Exp Pharmacol Physiol. 2007 May-Jun;34(5-6):450-6. doi: 10.1111/j.1440-1681.2007.04593.x.
• [9] Antisense therapy targeting MDM2 oncogene in prostate cancer: Effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11636-41. doi: 10.1073/pnas.1934692100. Epub 2003 Sep 16.
• [10] 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.