Details of the Drug Combination

General Information of Drug Combination (ID: DCBVOWG)

• Drug Combination Name: Cladribine + Marizomib
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Cladribine (DM3JDRP): Small molecular drug
  Marizomib (DME9QGW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 3.55
  Bliss Independence Score: 2.63
  Loewe Additivity Score: 2.27
  LHighest Single Agent (HSA) Score: 4.67

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Cladribine

Disease Entry	ICD 11	Status	REF
Hairy cell leukaemia	2A82.2	Approved	[2]
Multiple sclerosis	8A40	Phase 3	[3]
Relapsing-remitting multiple sclerosis	8A40.0	Phase 3	[4]

Cladribine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine deaminase (ADA)	TTLP57V	ADA_HUMAN	Inhibitor	[8]

Cladribine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[9]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[10]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[10]
Equilibrative nucleoside transporter 3 (SLC29A3)	DTZAWTH	S29A3_HUMAN	Substrate	[11]

Cladribine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Deoxycytidine kinase (DCK)	DE9FGNK	DCK_HUMAN	Metabolism	[12]

Cladribine Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[13]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[14]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Increases Expression	[15]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[16]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[13]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[16]
Lamin-B1 (LMNB1)	OT100T3P	LMNB1_HUMAN	Increases Cleavage	[16]
DNA cytosine-5)-methyltransferase 1 (DNMT1)	OTM2DGTK	DNMT1_HUMAN	Decreases Expression	[17]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[17]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Increases Phosphorylation	[18]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[19]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[20]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[19]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Increases Activity	[19]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[17]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[19]
Histone-lysine N-methyltransferase 2A (KMT2A)	OT9GLJI6	KMT2A_HUMAN	Increases Response To Substance	[21]

Indication(s) of Marizomib

Disease Entry	ICD 11	Status	REF
Glioblastoma of brain	2A00.00	Phase 3	[5]
Malignant glioma	2A00.0	Phase 1	[6]
Multiple myeloma	2A83	Phase 1	[6]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]

Marizomib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proteasome (PS)	TTU7ZMG	NOUNIPROTAC	Inhibitor	[22]

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] 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: 4799).
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] ClinicalTrials.gov (NCT03345095) A Phase III Trial of With Marizomib in Patients With Newly Diagnosed Glioblastoma (MIRAGE). U.S. National Institutes of Health.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Clinical pipeline report, company report or official report of Triphase Accelerator .
• [8] Cladribine: from the bench to the bedside--focus on hairy cell leukemia. Expert Rev Anticancer Ther. 2004 Oct;4(5):745-57.
• [9] Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides. Mol Cancer Ther. 2008 Sep;7(9):3092-102.
• [10] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [11] Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes. J Biol Chem. 2005 Apr 22;280(16):15880-7.
• [12] Potential mechanisms of action related to the efficacy and safety of cladribine. Mult Scler Relat Disord. 2019 May;30:176-186.
• [13] Expression and release of chemokines associated with apoptotic cell death in human promonocytic U937 cells and peripheral blood mononuclear cells. Eur J Immunol. 1999 Oct;29(10):3225-35. doi: 10.1002/(SICI)1521-4141(199910)29:10<3225::AID-IMMU3225>3.0.CO;2-0.
• [14] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [15] Paradoxical immunologic effects of 2-CdA therapy: comment on the article by Davis et al. Arthritis Rheum. 1998 Sep;41(9):1704-5. doi: 10.1002/1529-0131(199809)41:9<1704::AID-ART26>3.0.CO;2-9.
• [16] 2-Chlorodeoxyadenosine alone and in combination with cyclophosphamide and mitoxantrone induce apoptosis in B chronic lymphocytic leukemia cells in vivo. Cancer Detect Prev. 2004;28(6):433-42. doi: 10.1016/j.cdp.2004.08.001.
• [17] Comparative effects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells. Br J Nutr. 2012 Mar;107(6):781-90. doi: 10.1017/S0007114511003631. Epub 2011 Aug 1.
• [18] Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma. BMC Cancer. 2011 Jun 16;11:255. doi: 10.1186/1471-2407-11-255.
• [19] Cladribine induces apoptosis in human leukaemia cells by caspase-dependent and -independent pathways acting on mitochondria. Biochem J. 2001 Nov 1;359(Pt 3):537-46. doi: 10.1042/0264-6021:3590537.
• [20] Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activation. Biochem Pharmacol. 2003 Sep 1;66(5):711-24. doi: 10.1016/s0006-2952(03)00410-6.
• [21] In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype. Leukemia. 2004 Mar;18(3):521-9. doi: 10.1038/sj.leu.2403253.
• [22] 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.