Details of the Drug Combination

General Information of Drug Combination (ID: DCZMW6Z)

• Drug Combination Name: Risedronate + Marizomib
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Risedronate (DM5FLTY): Small molecular drug
  Marizomib (DME9QGW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 1.74
  Bliss Independence Score: 0.84
  Loewe Additivity Score: 2.99
  LHighest Single Agent (HSA) Score: 5.79

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Risedronate

Disease Entry	ICD 11	Status	REF
Bone Paget disease	N.A.	Approved	[2]
Osteoporosis	FB83.0	Approved	[2]
Paget's disease	FB85	Approved	[3]

Risedronate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Geranyltranstransferase (FDPS)	TTIKWV4	FPPS_HUMAN	Inhibitor	[7]

Risedronate Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Ras-related protein Rab-6A (RAB6A)	OTLS86J5	RAB6A_HUMAN	Decreases Prenylation	[8]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[9]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[9]
Ras-related protein Rap-1A (RAP1A)	OT5RH6TI	RAP1A_HUMAN	Decreases Prenylation	[10]

Indication(s) of Marizomib

Disease Entry	ICD 11	Status	REF
Glioblastoma of brain	2A00.00	Phase 3	[4]
Malignant glioma	2A00.0	Phase 1	[5]
Multiple myeloma	2A83	Phase 1	[5]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]

Marizomib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proteasome (PS)	TTU7ZMG	NOUNIPROTAC	Inhibitor	[11]

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] Risedronate FDA Label
• [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: 3176).
• [4] ClinicalTrials.gov (NCT03345095) A Phase III Trial of With Marizomib in Patients With Newly Diagnosed Glioblastoma (MIRAGE). U.S. National Institutes of Health.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Clinical pipeline report, company report or official report of Triphase Accelerator .
• [7] Activity of bisphosphonates against Trypanosoma brucei rhodesiense. J Med Chem. 2002 Jul 4;45(14):2904-14.
• [8] Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S-phase arrest, in human myeloma cells. Int J Cancer. 2006 Sep 15;119(6):1254-61. doi: 10.1002/ijc.21977.
• [9] Efficacy of the third-generation bisphosphonate risedronate alone and in combination with anticancer drugs against osteosarcoma cell lines. Anticancer Res. 2008 Jul-Aug;28(4B):2147-54.
• [10] Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity. Bone. 2001 Oct;29(4):336-43. doi: 10.1016/s8756-3282(01)00589-0.
• [11] 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.