Details of the Drug Combination

General Information of Drug Combination (ID: DCX22K8)

• Drug Combination Name: UCN-01 + Marizomib
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  UCN-01 (DMUNJZB): Small molecular drug
  Marizomib (DME9QGW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 3.71
  Bliss Independence Score: 2.99
  Loewe Additivity Score: 9.04
  LHighest Single Agent (HSA) Score: 11.3

Molecular Interaction Atlas of This Drug Combination

Indication(s) of UCN-01

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Phase 2	[2]

UCN-01 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Checkpoint kinase-1 (CHK1)	TTTU902	CHK1_HUMAN	Inhibitor	[7]

UCN-01 Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]

UCN-01 Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
3-phosphoinositide-dependent protein kinase 1 (PDPK1)	OTT09ZVP	PDPK1_HUMAN	Decreases Activity	[9]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Decreases Activity	[9]
Protein kinase C alpha type (PRKCA)	OT5UWNRD	KPCA_HUMAN	Decreases Activity	[9]
Ribosomal protein S6 kinase alpha-3 (RPS6KA3)	OTYJNNMD	KS6A3_HUMAN	Decreases Activity	[9]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Decreases Activity	[10]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[11]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Increases Expression	[12]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Increases Expression	[12]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[6]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[6]
BAG family molecular chaperone regulator 1 (BAG1)	OTRQNIA4	BAG1_HUMAN	Decreases Expression	[6]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Response To Substance	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Response To Substance	[14]

Indication(s) of Marizomib

Disease Entry	ICD 11	Status	REF
Glioblastoma of brain	2A00.00	Phase 3	[3]
Malignant glioma	2A00.0	Phase 1	[4]
Multiple myeloma	2A83	Phase 1	[4]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]

Marizomib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proteasome (PS)	TTU7ZMG	NOUNIPROTAC	Inhibitor	[15]

References

• [1] 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.
• [2] ClinicalTrials.gov (NCT00082017) UCN-01 (7-Hydroxystaurosporine) to Treat Relapsed T-Cell Lymphomas. U.S. National Institutes of Health.
• [3] ClinicalTrials.gov (NCT03345095) A Phase III Trial of With Marizomib in Patients With Newly Diagnosed Glioblastoma (MIRAGE). 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] Clinical pipeline report, company report or official report of Triphase Accelerator .
• [6] Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood. 2000 Jul 15;96(2):393-7.
• [7] Characterization of an inhibitory dynamic pharmacophore for the ERCC1-XPA interaction using a combined molecular dynamics and virtual screening app... J Mol Graph Model. 2009 Sep;28(2):113-30.
• [8] Pharmacogenomic importance of ABCG2. Pharmacogenomics. 2008 Aug;9(8):1005-9.
• [9] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [10] Cellular impedance assays for predictive preclinical drug screening of kinase inhibitor cardiovascular toxicity. Toxicol Sci. 2013 Oct;135(2):402-13. doi: 10.1093/toxsci/kft167. Epub 2013 Jul 28.
• [11] UCN-01 induces cytotoxicity toward human CLL cells through a p53-independent mechanism. Exp Hematol. 2001 Jun;29(6):703-8. doi: 10.1016/s0301-472x(01)00649-x.
• [12] The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin-dependent kinase inhibitors. Eur J Biochem. 2003 Dec;270(24):4809-22. doi: 10.1046/j.1432-1033.2003.03874.x.
• [13] The PARP inhibitor PJ34 causes a PARP1-independent, p21 dependent mitotic arrest. DNA Repair (Amst). 2011 Oct 10;10(10):1003-13. doi: 10.1016/j.dnarep.2011.07.006. Epub 2011 Aug 12.
• [14] A study of cytotoxic synergy of UCN-01 and flavopiridol in syngeneic pair of cell lines. Invest New Drugs. 2005 Aug;23(4):299-309. doi: 10.1007/s10637-005-1438-y.
• [15] Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr Cancer Drug Targets. 2011 Mar;11(3):254-84.