Details of the Drug Combination

General Information of Drug Combination (ID: DC96WY2)

• Drug Combination Name: MK-4827 + SNX-2112
• Indication: Malignant melanoma; Status: Investigative [1]
• Component Drugs:
  MK-4827 (DMLYGH4): Small molecular drug
  SNX-2112 (DMB5A80): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: UACC62
  Zero Interaction Potency (ZIP) Score: 1.56
  Bliss Independence Score: 0.39
  Loewe Additivity Score: 2.58
  LHighest Single Agent (HSA) Score: 3.88

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	[5]

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	[6]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[7]
Beta-glucuronidase (GUSB)	DEP54UE	BGLR_HUMAN	Metabolism	[7]

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	[8]

Indication(s) of SNX-2112

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

SNX-2112 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Heat shock protein 90 alpha (HSP90A)	TT78R5H	HS90A_HUMAN	Inhibitor	[4]

SNX-2112 Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Inhibitor of nuclear factor kappa-B kinase subunit alpha (CHUK)	OTLF4ZB1	IKKA_HUMAN	Decreases Expression	[9]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[9]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[9]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Decreases Expression	[9]
Endoplasmin (HSP90B1)	OT02XLBR	ENPL_HUMAN	Decreases Expression	[9]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[9]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[9]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Expression	[9]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[9]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[9]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[9]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[9]
Heat shock protein 75 kDa, mitochondrial (TRAP1)	OTNG0L8J	TRAP1_HUMAN	Decreases Expression	[9]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[9]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCQOSV7	ES2	Investigative	[10]
Breast carcinoma	DC863YI	ZR751	Investigative	[11]
Breast carcinoma	DC7HYCK	KPL1	Investigative	[11]
Breast carcinoma	DCA9DX4	OCUBM	Investigative	[11]
Carcinoma	DCJ44T6	OV90	Investigative	[11]
Carcinoma	DC6Z2I9	EFM192B	Investigative	[11]
Carcinoma	DCYZGOT	MDAMB436	Investigative	[11]
Colon adenocarcinoma	DC2ROHE	LOVO	Investigative	[11]
Colon carcinoma	DCQIQ79	RKO	Investigative	[11]
Invasive ductal carcinoma	DC0XGVK	T-47D	Investigative	[11]
Rectal adenocarcinoma	DCN643W	SW837	Investigative	[11]
Adenocarcinoma	DCIKDDC	CAOV3	Investigative	[1]
Adenocarcinoma	DC0L2WK	OVCAR3	Investigative	[1]
Adenocarcinoma	DCHW25O	A427	Investigative	[1]
Adenocarcinoma	DCZZOHN	NCIH1650	Investigative	[1]
Adenocarcinoma	DCVNSN7	NCIH2122	Investigative	[1]
Adenocarcinoma	DCNL3AP	NCIH23	Investigative	[1]
Adenocarcinoma	DCFNTKC	NCIH520	Investigative	[1]
Adenocarcinoma	DCYAYYW	COLO320DM	Investigative	[1]
Adenocarcinoma	DCVFKNW	DLD1	Investigative	[1]
Adenocarcinoma	DCI0IQB	HCT116	Investigative	[1]
Adenocarcinoma	DC8VEIK	HT29	Investigative	[1]
Adenocarcinoma	DCEKHIK	SW-620	Investigative	[1]
Amelanotic melanoma	DC8ESVA	A2058	Investigative	[1]
Germ cell tumour	DCJT3AG	PA1	Investigative	[1]
Large cell lung carcinoma	DCFXI48	NCI-H460	Investigative	[1]
Malignant melanoma	DCBPB7L	HT144	Investigative	[1]
Malignant melanoma	DCCYUYS	SKMEL30	Investigative	[1]
Malignant melanoma	DC8Q5PN	A375	Investigative	[1]
Mesothelioma	DCX2XY6	MSTO	Investigative	[1]
Non small cell carcinoma	DCJL92N	SKMES1	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DCHMI4S	A2780	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCPDGB7	SK-OV-3	Investigative	[1]
Prostate carcinoma	DCPGJ6F	LNCAP	Investigative	[1]
Prostate carcinoma	DCWDV0K	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] Heat shock protein 90: inhibitors in clinical trials. J Med Chem. 2010 Jan 14;53(1):3-17.
• [5] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [6] 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.
• [7] Summary of FDA-approved anticancer cytotoxic drugs at May 2019.
• [8] 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.
• [9] The Hsp90 inhibitor SNX-2112, induces apoptosis in multidrug resistant K562/ADR cells through suppression of Akt/NF-B and disruption of mitochondria-dependent pathways. Chem Biol Interact. 2013 Sep 5;205(1):1-10. doi: 10.1016/j.cbi.2013.06.007. Epub 2013 Jun 15.
• [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.
• [11] 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.