Details of the Drug Combination

General Information of Drug Combination (ID: DC4ADUK)

• Drug Combination Name: SCH 727965 + GSK525762
• Indication: Breast and ovarian cancer syndrome; Status: Investigative [1]
• Component Drugs:
  SCH 727965 (DMCJLD1): Small molecular drug
  GSK525762 (DMPAWBN): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: UWB1289+BRCA1
  Zero Interaction Potency (ZIP) Score: 1.34
  Bliss Independence Score: 2.33
  Loewe Additivity Score: 1.39
  LHighest Single Agent (HSA) Score: 2.52

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 GSK525762

Disease Entry	ICD 11	Status	REF
Haematological malignancy	2B33.Y	Phase 1	[3]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]

GSK525762 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bromodomain-containing protein 4 (BRD4)	TTRA6BO	BRD4_HUMAN	Modulator	[9]
Bromodomain and extraterminal domain protein (BET)	TTE4BSY	NOUNIPROTAC	Inhibitor	[3]

GSK525762 Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Increases Expression	[10]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Expression	[11]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Decreases Expression	[11]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[11]
Protein-lysine 6-oxidase (LOX)	OT1C2HIU	LYOX_HUMAN	Decreases Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[12]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[12]
Carbonic anhydrase 9 (CA9)	OTNA51XT	CAH9_HUMAN	Decreases Expression	[8]
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3)	OT25JBA3	F263_HUMAN	Increases Expression	[8]
Protein GREB1 (GREB1)	OTU6ZA26	GREB1_HUMAN	Decreases Expression	[11]
Endothelial PAS domain-containing protein 1 (EPAS1)	OTRE3O8U	EPAS1_HUMAN	Increases Expression	[8]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast and ovarian cancer syndrome	DCCPGB4	UWB1289	Investigative	[1]
Breast carcinoma	DC5JBBF	OCUBM	Investigative	[1]
Carcinoma	DCQCSBE	OV90	Investigative	[1]
Carcinoma	DCD3N8V	MDAMB436	Investigative	[1]
Invasive ductal carcinoma	DCRQZ86	T-47D	Investigative	[1]
Adenocarcinoma	DC5DZDR	NCIH2122	Investigative	[13]
Amelanotic melanoma	DC23MYV	A2058	Investigative	[13]
Malignant melanoma	DCOO6US	RPMI7951	Investigative	[13]
Ovarian endometrioid adenocarcinoma	DCR9QWK	A2780	Investigative	[13]

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: 7379).
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] 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: 7033).
• [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] The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer. Oncogene. 2017 Jan 5;36(1):122-132. doi: 10.1038/onc.2016.184. Epub 2016 Jun 13.
• [9] Targeting bromodomains: epigenetic readers of lysine acetylation.Nat Rev Drug Discov.2014 May;13(5):337-56.
• [10] Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem. 2011 Jun 9;54(11):3827-38.
• [11] An epigenomic approach to therapy for tamoxifen-resistant breast cancer. Cell Res. 2014 Jul;24(7):809-19. doi: 10.1038/cr.2014.71. Epub 2014 May 30.
• [12] MCM5 as a target of BET inhibitors in thyroid cancer cells. Endocr Relat Cancer. 2016 Apr;23(4):335-47. doi: 10.1530/ERC-15-0322. Epub 2016 Feb 24.
• [13] 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.