Details of the Drug Combination

General Information of Drug Combination (ID: DCWYKA5)

• Drug Combination Name: PI-103 + Marizomib
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  PI-103 (DMEK4TJ): Small molecular drug
  Marizomib (DME9QGW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 3.5
  Bliss Independence Score: 3.05
  Loewe Additivity Score: 2.91
  LHighest Single Agent (HSA) Score: 9.02

Molecular Interaction Atlas of This Drug Combination

Indication(s) of PI-103

Disease Entry	ICD 11	Status	REF
Haematological malignancy	2B33.Y	Investigative	[2]

PI-103 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
PI3-kinase gamma (PIK3CG)	TTHBTOP	PK3CG_HUMAN	Inhibitor	[6]

PI-103 Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[7]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[8]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[8]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[9]
Carbonic anhydrase 9 (CA9)	OTNA51XT	CAH9_HUMAN	Decreases Phosphorylation	[10]

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	[11]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [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: 5701).
• [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] The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9.
• [7] PI3K inhibition enhances doxorubicin-induced apoptosis in sarcoma cells. PLoS One. 2012;7(12):e52898. doi: 10.1371/journal.pone.0052898. Epub 2012 Dec 31.
• [8] PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res. 2010 Dec;30(12):4951-8.
• [9] The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells. Int J Cancer. 2010 Apr 1;126(7):1549-61. doi: 10.1002/ijc.24926.
• [10] GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1 (HIF-1) pathways. J Clin Endocrinol Metab. 2011 Dec;96(12):E1934-43. doi: 10.1210/jc.2011-1426. Epub 2011 Oct 12.
• [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.