Details of the Drug Combination

General Information of Drug Combination (ID: DC3CSQQ)

• Drug Combination Name: Estramustine + MK-4827
• Indication: Amelanotic melanoma; Status: Investigative [1]
• Component Drugs:
  Estramustine (DMWTAOI): Small molecular drug
  MK-4827 (DMLYGH4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: A2058
  Zero Interaction Potency (ZIP) Score: 4.64
  Bliss Independence Score: 8.64
  Loewe Additivity Score: 9.1
  LHighest Single Agent (HSA) Score: 10.9

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-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	[9]

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	[10]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[11]
Beta-glucuronidase (GUSB)	DEP54UE	BGLR_HUMAN	Metabolism	[11]

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	[12]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCCQWD8	ES2	Investigative	[13]
Breast and ovarian cancer syndrome	DCVDU6R	UWB1289	Investigative	[14]
Breast and ovarian cancer syndrome	DC6QP93	UWB1289+BRCA1	Investigative	[14]
Breast carcinoma	DCSBN29	OCUBM	Investigative	[14]
Carcinoma	DC5PXLZ	EFM192B	Investigative	[14]
Carcinoma	DCHGZDS	MDAMB436	Investigative	[14]
Colon adenocarcinoma	DCMQAS5	LOVO	Investigative	[14]
Colon carcinoma	DCBTL6K	RKO	Investigative	[14]
Rectal adenocarcinoma	DC44DUE	SW837	Investigative	[14]
Adenocarcinoma	DCFQCRE	CAOV3	Investigative	[1]
Adenocarcinoma	DC5B0CG	A427	Investigative	[1]
Adenocarcinoma	DCGOSKE	NCIH1650	Investigative	[1]
Adenocarcinoma	DCXQNEO	NCIH2122	Investigative	[1]
Adenocarcinoma	DC9PTV3	NCIH23	Investigative	[1]
Adenocarcinoma	DCWEHI9	NCIH520	Investigative	[1]
Adenocarcinoma	DC3WP0U	COLO320DM	Investigative	[1]
Adenocarcinoma	DCMEYC8	DLD1	Investigative	[1]
Adenocarcinoma	DCSUO6D	HCT116	Investigative	[1]
Adenocarcinoma	DCEJDAW	HT29	Investigative	[1]
Adenocarcinoma	DCNCC3T	SW-620	Investigative	[1]
Germ cell tumour	DC4R6GG	PA1	Investigative	[1]
Large cell lung carcinoma	DCFNRK6	NCI-H460	Investigative	[1]
Malignant melanoma	DCPS87M	A375	Investigative	[1]
Malignant melanoma	DC806PV	RPMI7951	Investigative	[1]
Malignant melanoma	DCURHSP	SKMEL30	Investigative	[1]
Malignant melanoma	DC8KZKY	UACC62	Investigative	[1]
Mesothelioma	DCRQ1ZE	MSTO	Investigative	[1]
Non small cell carcinoma	DC3QHQH	SKMES1	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DCB5BI2	A2780	Investigative	[1]
Ovarian serous cystadenocarcinoma	DC2EAWX	SK-OV-3	Investigative	[1]
Prostate carcinoma	DC1VSSS	LNCAP	Investigative	[1]
Prostate carcinoma	DCN438M	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] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [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] 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] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [10] 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.
• [11] Summary of FDA-approved anticancer cytotoxic drugs at May 2019.
• [12] 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.
• [13] 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.
• [14] 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.