Details of the Drug Combination

General Information of Drug Combination (ID: DC9ZVQB)

• Drug Combination Name: SCH 727965 + MK-4827
• Indication: Amelanotic melanoma; Status: Investigative [1]
• Component Drugs:
  SCH 727965 (DMCJLD1): Small molecular drug
  MK-4827 (DMLYGH4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: A2058
  Zero Interaction Potency (ZIP) Score: 19.68
  Bliss Independence Score: 19.91
  Loewe Additivity Score: 21.1
  LHighest Single Agent (HSA) Score: 23.73

Molecular Interaction Atlas of This Drug Combination

Indication(s) of SCH 727965

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Discontinued in Phase 3	[2]

SCH 727965 Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 9 (CDK9)	TT1LVF2	CDK9_HUMAN	Inhibitor	[5]
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[5]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[5]

SCH 727965 Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[6]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[6]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Decreases Expression	[7]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[7]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[7]
Fanconi anemia group D2 protein (FANCD2)	OTVEB5LF	FACD2_HUMAN	Decreases Expression	[7]
Cyclin-dependent kinase 12 (CDK12)	OTZUDGNU	CDK12_HUMAN	Decreases Activity	[7]

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	[8]

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	[9]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[10]
Beta-glucuronidase (GUSB)	DEP54UE	BGLR_HUMAN	Metabolism	[10]

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	[11]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCO7WUL	ES2	Investigative	[12]
Breast and ovarian cancer syndrome	DC7N05K	UWB1289	Investigative	[13]
Breast and ovarian cancer syndrome	DCLGDG3	UWB1289+BRCA1	Investigative	[13]
Breast carcinoma	DCNWV2J	ZR751	Investigative	[13]
Breast carcinoma	DCA24FU	KPL1	Investigative	[13]
Breast carcinoma	DC697WH	OCUBM	Investigative	[13]
Carcinoma	DC0HB0P	EFM192B	Investigative	[13]
Carcinoma	DCW1ILJ	MDAMB436	Investigative	[13]
Colon adenocarcinoma	DCMZKFN	LOVO	Investigative	[13]
Colon carcinoma	DCXSUXF	RKO	Investigative	[13]
Invasive ductal carcinoma	DCEGW23	T-47D	Investigative	[13]
Adenocarcinoma	DC696X1	CAOV3	Investigative	[1]
Adenocarcinoma	DC1DDQ1	OVCAR3	Investigative	[1]
Adenocarcinoma	DCHTTY5	A427	Investigative	[1]
Adenocarcinoma	DCLPMDM	NCIH2122	Investigative	[1]
Adenocarcinoma	DCD6ULY	NCIH23	Investigative	[1]
Adenocarcinoma	DCQ97H9	NCIH520	Investigative	[1]
Adenocarcinoma	DCNYKAI	COLO320DM	Investigative	[1]
Adenocarcinoma	DCNDJ48	DLD1	Investigative	[1]
Adenocarcinoma	DC4LTRP	HCT116	Investigative	[1]
Adenocarcinoma	DCGV3UZ	HT29	Investigative	[1]
Adenocarcinoma	DC82UBL	SW-620	Investigative	[1]
Germ cell tumour	DC9GIIF	PA1	Investigative	[1]
Large cell lung carcinoma	DC61CRJ	NCI-H460	Investigative	[1]
Malignant melanoma	DCBOLHQ	A375	Investigative	[1]
Malignant melanoma	DCQBEQC	HT144	Investigative	[1]
Malignant melanoma	DCZ1MPD	RPMI7951	Investigative	[1]
Malignant melanoma	DCO3GRW	SKMEL30	Investigative	[1]
Malignant melanoma	DC2DTRI	UACC62	Investigative	[1]
Mesothelioma	DCEFV8W	MSTO	Investigative	[1]
Non small cell carcinoma	DC7XKKZ	SKMES1	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DC8ODSZ	A2780	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCPQ91K	SK-OV-3	Investigative	[1]
Prostate carcinoma	DC0U3H4	LNCAP	Investigative	[1]
Prostate carcinoma	DCSWNY4	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] 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: 7379).
• [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] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [6] Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010 Aug;9(8):2344-53. doi: 10.1158/1535-7163.MCT-10-0324. Epub 2010 Jul 27.
• [7] CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep. 2016 Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077.
• [8] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [9] 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.
• [10] Summary of FDA-approved anticancer cytotoxic drugs at May 2019.
• [11] 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.
• [12] 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.
• [13] 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.