Details of the Drug Combination

General Information of Drug Combination (ID: DCE2PDD)

• Drug Combination Name: Alprostadil + Marizomib
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Alprostadil (DMWH7NQ): Small molecular drug
  Marizomib (DME9QGW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 4.21
  Bliss Independence Score: 3.96
  Loewe Additivity Score: 0.37
  LHighest Single Agent (HSA) Score: 1.16

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Alprostadil

Disease Entry	ICD 11	Status	REF
Aorta coarctation	N.A.	Approved	[2]
Diabetic foot ulcer	BD54	Approved	[3]
Erectile dysfunction	HA01.1	Approved	[4]
Pulmonary hypertension	BB01	Approved	[2]
Tetralogy of fallot	N.A.	Approved	[2]

Alprostadil Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin E2 receptor EP2 (PTGER2)	TT1ZAVI	PE2R2_HUMAN	Agonist	[3]
Thromboxane A2 receptor (TBXA2R)	TT2O84V	TA2R_HUMAN	Modulator	[9]

Alprostadil Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[10]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 2A1 (SLCO2A1)	DT021JD	SO2A1_HUMAN	Substrate	[12]
Organic anion transporting polypeptide 3A1 (SLCO3A1)	DTVNRXW	SO3A1_HUMAN	Substrate	[13]

Alprostadil Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Prostaglandin dehydrogenase 1 (HPGD)	DEHKSC6	PGDH_HUMAN	Metabolism	[14]

Alprostadil Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Prostaglandin D2 receptor (PTGDR)	OT92UR1A	PD2R_HUMAN	Affects Binding	[15]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[16]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[16]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[17]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Phosphorylation	[18]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[19]
Vasopressin V1a receptor (AVPR1A)	OTKR8AFL	V1AR_HUMAN	Increases ADR	[20]

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	[21]

References

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• [2] Alprostadil FDA Label
• [3] Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006 Nov;11(4):709-24.
• [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: 1882).
• [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] Arsenic trioxide-mediated antiplatelet activity: pivotal role of the phospholipase C gamma 2-protein kinase C-p38 MAPK cascade. Transl Res. 2010 Feb;155(2):97-108. doi: 10.1016/j.trsl.2009.08.005. Epub 2009 Sep 15.
• [9] Flow after prostaglandin E1 is mediated by receptor-coupled adenylyl cyclase in human anterior segments. Invest Ophthalmol Vis Sci. 1999 Oct;40(11):2622-6.
• [10] The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9.
• [11] Prostaglandin transporter (OATP2A1/SLCO2A1) contributes to local disposition of eicosapentaenoic acid-derived PGE3. Prostaglandins Other Lipid Mediat. 2016 Jan;122:10-7.
• [12] Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT). J Clin Invest. 1996 Sep 1;98(5):1142-9.
• [13] Molecular characterization of human and rat organic anion transporter OATP-D. Am J Physiol Renal Physiol. 2003 Dec;285(6):F1188-97.
• [14] Effect of calcium ionophore A23187 on prostaglandin synthase type 2 and 15-hydroxy-prostaglandin dehydrogenase expression in human chorion trophoblast cells. Am J Obstet Gynecol. 2008 Nov;199(5):554.e1-8.
• [15] Characterization of the recombinant human prostanoid DP receptor and identification of L-644,698, a novel selective DP agonist. Br J Pharmacol. 1998 Apr;123(7):1317-24.
• [16] Catecholamine and renin-angiotensin response during controlled hypotension induced by prostaglandin E1 combined with hemodilution during isoflurane anesthesia. J Clin Anesth. 1997 Jun;9(4):321-7. doi: 10.1016/s0952-8180(97)00011-1.
• [17] Effects of prostaglandin E1, dobutamine and placebo on hemodynamic, renal and neurohumoral variables in patients with advanced heart failure. Jpn Heart J. 1999 May;40(3):321-34. doi: 10.1536/jhj.40.321.
• [18] Characterization of agonist stimulation of cAMP-dependent protein kinase and G protein-coupled receptor kinase phosphorylation of the beta2-adrenergic receptor using phosphoserine-specific antibodies. Mol Pharmacol. 2004 Jan;65(1):196-206. doi: 10.1124/mol.65.1.196.
• [19] Short-term effects of levosimendan and prostaglandin E1 on hemodynamic parameters and B-type natriuretic peptide levels in patients with decompensated chronic heart failure. Eur J Heart Fail. 2005 Dec;7(7):1156-63. doi: 10.1016/j.ejheart.2005.05.001. Epub 2005 Aug 5.
• [20] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [21] 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.