Details of the Drug Combination

General Information of Drug Combination (ID: DC3GETX)

• Drug Combination Name: GSK525762 + Lomustine
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  GSK525762 (DMPAWBN): Small molecular drug
  Lomustine (DMMWSUL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HCT116
  Zero Interaction Potency (ZIP) Score: 11.7
  Bliss Independence Score: 9.34
  Loewe Additivity Score: 1.18
  LHighest Single Agent (HSA) Score: 10.56

Molecular Interaction Atlas of This Drug Combination

Indication(s) of GSK525762

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

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	[7]
Bromodomain and extraterminal domain protein (BET)	TTE4BSY	NOUNIPROTAC	Inhibitor	[2]

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

Indication(s) of Lomustine

Disease Entry	ICD 11	Status	REF
Brain cancer	2A00	Approved	[4]
Central nervous system neoplasm	N.A.	Approved	[5]
Primitive neuroectodermal tumor	N.A.	Approved	[5]
Classic Hodgkin lymphoma	N.A.	Investigative	[5]

Lomustine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Inhibitor	[11]

Lomustine Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Suppressor of cytokine signaling 1 (SOCS1)	OTWA9KFU	SOCS1_HUMAN	Decreases Expression	[12]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[13]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[14]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[15]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[16]
DNA polymerase eta (POLH)	OTN07WXU	POLH_HUMAN	Increases Expression	[17]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Decreases Response To Substance	[18]
Stathmin (STMN1)	OTDJ4RV0	STMN1_HUMAN	Affects Response To Substance	[19]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast carcinoma	DC2TT9H	OCUBM	Investigative	[20]
Mesothelioma	DCGJ5EZ	MSTO	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DCA7CLG	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] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 7033).
• [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: 7214).
• [5] Lomustine FDA Label
• [6] 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.
• [7] Targeting bromodomains: epigenetic readers of lysine acetylation.Nat Rev Drug Discov.2014 May;13(5):337-56.
• [8] Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem. 2011 Jun 9;54(11):3827-38.
• [9] 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.
• [10] 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.
• [11] Synthesis and evaluation of ethylnitrosoureas of substituted naphthalimides as anticancer compounds. Acta Pol Pharm. 2007 Jan-Feb;64(1):27-33.
• [12] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [13] Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs. Int J Cancer. 2004 Sep 10;111(4):484-93. doi: 10.1002/ijc.20230.
• [14] High-content imaging-based BAC-GFP toxicity pathway reporters to assess chemical adversity liabilities. Arch Toxicol. 2017 Mar;91(3):1367-1383. doi: 10.1007/s00204-016-1781-0. Epub 2016 Jun 29.
• [15] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [16] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [17] Translesion polymerase is upregulated by cancer therapeutics and confers anticancer drug resistance. Cancer Res. 2014 Oct 1;74(19):5585-96. doi: 10.1158/0008-5472.CAN-14-0953. Epub 2014 Aug 14.
• [18] Human osteosarcoma xenografts and their sensitivity to chemotherapy. Pathol Oncol Res. 2004;10(3):133-41. doi: 10.1007/BF03033741. Epub 2004 Sep 25.
• [19] The 1p-encoded protein stathmin and resistance of malignant gliomas to nitrosoureas. J Natl Cancer Inst. 2007 Apr 18;99(8):639-52. doi: 10.1093/jnci/djk135.
• [20] 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.