Details of the Drug Combination

General Information of Drug Combination (ID: DCYRSFL)

• Drug Combination Name: Estramustine + MK-1775
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Estramustine (DMWTAOI): Small molecular drug
  MK-1775 (DM3WDZ5): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: A427
  Zero Interaction Potency (ZIP) Score: 5.67
  Bliss Independence Score: 4.13
  Loewe Additivity Score: 9.32
  LHighest Single Agent (HSA) Score: 10.35

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Estramustine

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Approved	[2]

Estramustine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estramustine binding protein (EMBP)	TTSBFYK	NOUNIPROTAC	Binder	[5]

Estramustine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]

Estramustine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Keratin, type I cytoskeletal 18 (KRT18)	OTVLQFIP	K1C18_HUMAN	Increases Expression	[7]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Increases Phosphorylation	[8]

Indication(s) of MK-1775

Disease Entry	ICD 11	Status	REF
Ovarian cancer	2C73	Phase 2	[3]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]

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	[10]

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	[9]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Response To Substance	[9]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCXBAE9	ES2	Investigative	[11]
Breast and ovarian cancer syndrome	DC8RIYX	UWB1289	Investigative	[12]
Breast carcinoma	DC05PAU	OCUBM	Investigative	[12]
Carcinoma	DCL04CS	EFM192B	Investigative	[12]
Colon adenocarcinoma	DCFP73J	LOVO	Investigative	[12]
Invasive ductal carcinoma	DCCGIN3	T-47D	Investigative	[12]
Adenocarcinoma	DC32TT3	CAOV3	Investigative	[1]
Adenocarcinoma	DCMW6FP	NCIH2122	Investigative	[1]
Adenocarcinoma	DC5Q9HY	NCIH520	Investigative	[1]
Adenocarcinoma	DCSF1LK	COLO320DM	Investigative	[1]
Adenocarcinoma	DC61LSG	DLD1	Investigative	[1]
Adenocarcinoma	DCA5QO6	HT29	Investigative	[1]
Adenocarcinoma	DCIZKVL	SW-620	Investigative	[1]
Amelanotic melanoma	DCASYQW	A2058	Investigative	[1]
Germ cell tumour	DCS0RVF	PA1	Investigative	[1]
Malignant melanoma	DCLJNJ2	A375	Investigative	[1]
Malignant melanoma	DCO8IQQ	HT144	Investigative	[1]
Malignant melanoma	DCS0WS5	RPMI7951	Investigative	[1]
Malignant melanoma	DCE6FX0	SKMEL30	Investigative	[1]
Mesothelioma	DC9SD03	MSTO	Investigative	[1]
Non small cell carcinoma	DC8484L	SKMES1	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DCJBZYW	A2780	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] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [3] 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).
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Estramustine binding protein in primary tumours and metastases of malignant melanoma. Melanoma Res. 1994 Dec;4(6):401-5.
• [6] Activity of docetaxel with or without estramustine phosphate versus mitoxantrone in androgen dependent and independent human prostate cancer xenografts. J Urol. 2003 May;169(5):1729-34.
• [7] Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Br J Cancer. 2006 Jun 5;94(11):1592-8. doi: 10.1038/sj.bjc.6603129.
• [8] Induction of apoptosis by estramustine phosphate mediated by phosphorylation of bcl-2. J Neurooncol. 2001 Aug;54(1):23-9. doi: 10.1023/a:1012566601485.
• [9] 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.
• [10] 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.
• [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.