Details of the Drug Combination

General Information of Drug Combination (ID: DCMF9SU)

• Drug Combination Name: Rofecoxib + Marizomib
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Rofecoxib (DM3P5DA): Small molecular drug
  Marizomib (DME9QGW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 4.75
  Bliss Independence Score: 3.64
  Loewe Additivity Score: 0.72
  LHighest Single Agent (HSA) Score: 2.73

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Rofecoxib

Disease Entry	ICD 11	Status	REF
Osteoarthritis	FA00-FA05	Approved	[2]

Rofecoxib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase 2 (COX-2)	TTVKILB	PGH2_HUMAN	Inhibitor	[7]

Rofecoxib Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[9]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[8]

Rofecoxib Interacts with 92 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[12]
Prostaglandin G/H synthase 1 (PTGS1)	OTHCRLEC	PGH1_HUMAN	Decreases Expression	[13]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[14]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[6]
Suppressor of cytokine signaling 3 (SOCS3)	OTY183WJ	SOCS3_HUMAN	Increases Expression	[6]
Ephrin type-B receptor 6 (EPHB6)	OTKNN6GC	EPHB6_HUMAN	Decreases Expression	[6]
Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B)	OTWQQ08W	LX15B_HUMAN	Affects Expression	[6]
Tetraspanin-2 (TSPAN2)	OTTDPQF1	TSN2_HUMAN	Decreases Expression	[6]
SH2 domain-containing protein 1A (SH2D1A)	OTLU49I5	SH21A_HUMAN	Decreases Expression	[6]
Filamin-B (FLNB)	OTPCOYL6	FLNB_HUMAN	Increases Expression	[6]
Annexin A9 (ANXA9)	OTKNYMU2	ANXA9_HUMAN	Decreases Expression	[6]
Metastasis-associated protein MTA2 (MTA2)	OTCCYIQJ	MTA2_HUMAN	Decreases Expression	[6]
Neurofascin (NFASC)	OTBDUXZT	NFASC_HUMAN	Decreases Expression	[6]
Angiopoietin-related protein 1 (ANGPTL1)	OTXIN6V5	ANGL1_HUMAN	Decreases Expression	[6]
Integrin beta-like protein 1 (ITGBL1)	OTJDHE17	ITGBL_HUMAN	Affects Expression	[6]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[6]
Complement C3 (C3)	OTCH5GS0	CO3_HUMAN	Increases Expression	[6]
Transferrin receptor protein 1 (TFRC)	OT8ZPBDL	TFR1_HUMAN	Affects Expression	[6]
Annexin A1 (ANXA1)	OT5OFDJC	ANXA1_HUMAN	Affects Expression	[6]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[6]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[6]
Growth-regulated alpha protein (CXCL1)	OT3WCTZV	GROA_HUMAN	Affects Expression	[6]
Clusterin (CLU)	OTQGG0JM	CLUS_HUMAN	Increases Expression	[6]
Annexin A3 (ANXA3)	OTDD8OI7	ANXA3_HUMAN	Increases Expression	[6]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[6]
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)	OTPWI88U	CEAM1_HUMAN	Affects Expression	[6]
Hepatocyte growth factor (HGF)	OTGHUA23	HGF_HUMAN	Decreases Expression	[6]
Phospholipase A2, membrane associated (PLA2G2A)	OT1NY7BF	PA2GA_HUMAN	Affects Expression	[6]
Fatty acid-binding protein, adipocyte (FABP4)	OT3DKFOU	FABP4_HUMAN	Decreases Expression	[6]
15-hydroxyprostaglandin dehydrogenase (HPGD)	OTYZI6JB	PGDH_HUMAN	Decreases Expression	[6]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Affects Expression	[6]
Interleukin-1 receptor antagonist protein (IL1RN)	OT308CBE	IL1RA_HUMAN	Increases Expression	[6]
Cadherin-2 (CDH2)	OTH0Y56P	CADH2_HUMAN	Affects Expression	[6]
Atrial natriuretic peptide receptor 2 (NPR2)	OT4651SI	ANPRB_HUMAN	Decreases Expression	[6]
Ras GTPase-activating protein 1 (RASA1)	OTZJ3LP4	RASA1_HUMAN	Affects Expression	[6]
Myelin and lymphocyte protein (MAL)	OTBM30SW	MAL_HUMAN	Increases Expression	[6]
Cadherin-3 (CDH3)	OTKNLQU7	CADH3_HUMAN	Increases Expression	[6]
Trans-acting T-cell-specific transcription factor GATA-3 (GATA3)	OTGP7D5Y	GATA3_HUMAN	Decreases Expression	[6]
Tenascin (TNC)	OTK4FSHR	TENA_HUMAN	Increases Expression	[6]
Ephrin type-A receptor 3 (EPHA3)	OTZJF3ML	EPHA3_HUMAN	Decreases Expression	[6]
Nitric oxide synthase 1 (NOS1)	OT7M8XVG	NOS1_HUMAN	Affects Expression	[6]
Protein PML (PML)	OT6SM2GD	PML_HUMAN	Increases Expression	[6]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Increases Expression	[6]
ETS translocation variant 5 (ETV5)	OTE2OBM4	ETV5_HUMAN	Decreases Expression	[6]
Phosphatidylinositol 4-kinase alpha (PI4KA)	OT2L2G6C	PI4KA_HUMAN	Decreases Expression	[6]
Leukemia inhibitory factor receptor (LIFR)	OT36W9O5	LIFR_HUMAN	Decreases Expression	[6]
Prostaglandin E2 receptor EP3 subtype (PTGER3)	OTQODQUN	PE2R3_HUMAN	Decreases Expression	[6]
Homeobox protein MOX-2 (MEOX2)	OTKZCJCB	MEOX2_HUMAN	Decreases Expression	[6]
Nuclear receptor ROR-gamma (RORC)	OTUBFRPC	RORG_HUMAN	Decreases Expression	[6]
Cysteine-rich secretory protein 3 (CRISP3)	OTBSWMPL	CRIS3_HUMAN	Increases Expression	[6]
Paired mesoderm homeobox protein 1 (PRRX1)	OTTZK5G8	PRRX1_HUMAN	Affects Expression	[6]
Afadin (AFDN)	OTTRU341	AFAD_HUMAN	Affects Expression	[6]
Fractalkine (CX3CL1)	OTPLGI0E	X3CL1_HUMAN	Affects Expression	[6]
Insulinoma-associated protein 1 (INSM1)	OTG8RV8E	INSM1_HUMAN	Decreases Expression	[6]
Collagen alpha-1(XIV) chain (COL14A1)	OTLNJ13O	COEA1_HUMAN	Decreases Expression	[6]
MBT domain-containing protein 1 (MBTD1)	OT2P6943	MBTD1_HUMAN	Decreases Expression	[6]
Aldehyde oxidase (AOX1)	OT2FZP6H	AOXA_HUMAN	Decreases Expression	[6]
Myocyte-specific enhancer factor 2C (MEF2C)	OTZGF1Y5	MEF2C_HUMAN	Affects Expression	[6]
Desmocollin-1 (DSC1)	OTNII6GZ	DSC1_HUMAN	Affects Expression	[6]
Periostin (POSTN)	OTWP62UA	POSTN_HUMAN	Affects Expression	[6]
Angiopoietin-1 (ANGPT1)	OTVZ1NG3	ANGP1_HUMAN	Decreases Expression	[6]
Corneodesmosin (CDSN)	OTQW4HV6	CDSN_HUMAN	Affects Expression	[6]
Microtubule-associated protein RP/EB family member 2 (MAPRE2)	OTAE3MX4	MARE2_HUMAN	Decreases Expression	[6]
Transcriptional enhancer factor TEF-3 (TEAD4)	OTJS0T2B	TEAD4_HUMAN	Increases Expression	[6]
Forkhead box protein D1 (FOXD1)	OT80PRHS	FOXD1_HUMAN	Decreases Expression	[6]
Rho GTPase-activating protein 29 (ARHGAP29)	OT8JH4TY	RHG29_HUMAN	Decreases Expression	[6]
Inactive N-acetylated-alpha-linked acidic dipeptidase-like protein 2 (NAALADL2)	OT2HOGPQ	NADL2_HUMAN	Decreases Expression	[6]
Collectin-12 (COLEC12)	OTIQTK9G	COL12_HUMAN	Decreases Expression	[6]
Adhesion G-protein coupled receptor F1 (ADGRF1)	OTRAOBYH	AGRF1_HUMAN	Affects Expression	[6]
E3 ubiquitin-protein ligase RNF144B (RNF144B)	OTN7FCDE	R144B_HUMAN	Increases Expression	[6]
Adhesion G-protein coupled receptor G6 (ADGRG6)	OTY2UBXO	AGRG6_HUMAN	Affects Expression	[6]
Neuronal PAS domain-containing protein 3 (NPAS3)	OT8D1ILB	NPAS3_HUMAN	Increases Expression	[6]
Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3)	OTEH9HGE	CA2D3_HUMAN	Decreases Expression	[6]
LIM homeobox transcription factor 1-alpha (LMX1A)	OTEEYD5L	LMX1A_HUMAN	Increases Expression	[6]
Secreted frizzled-related protein 3 (FRZB)	OTTO3DPY	SFRP3_HUMAN	Affects Expression	[6]
Protein lifeguard 2 (FAIM2)	OT6QINVO	LFG2_HUMAN	Decreases Expression	[6]
Transmembrane protease serine 4 (TMPRSS4)	OTCCGY2K	TMPS4_HUMAN	Increases Expression	[6]
FAS-associated factor 1 (FAF1)	OTGAMLM4	FAF1_HUMAN	Affects Expression	[6]
A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8)	OT2KFY1S	ATS8_HUMAN	Affects Expression	[6]
Krueppel-like factor 12 (KLF12)	OTVH4KD4	KLF12_HUMAN	Affects Expression	[6]
E3 ubiquitin-protein ligase TRIM17 (TRIM17)	OTUJZUOS	TRI17_HUMAN	Affects Expression	[6]
Prostacyclin synthase (PTGIS)	OTT3RW6N	PTGIS_HUMAN	Decreases Expression	[13]
Tissue-type plasminogen activator (PLAT)	OTQPDNAB	TPA_HUMAN	Increases Expression	[15]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[16]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Decreases Expression	[17]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Increases Expression	[15]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[17]
Stromelysin-1 (MMP3)	OTGBI74Z	MMP3_HUMAN	Increases Expression	[15]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[15]
Protachykinin-1 (TAC1)	OTM842YW	TKN1_HUMAN	Increases Expression	[18]
Metalloproteinase inhibitor 3 (TIMP3)	OTDGQAD1	TIMP3_HUMAN	Decreases Expression	[15]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[19]

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	[20]

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: 2893).
• [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] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [7] Privileged structures: a useful concept for the rational design of new lead drug candidates. Mini Rev Med Chem. 2007 Nov;7(11):1108-19.
• [8] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [9] Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects. Br J Clin Pharmacol. 2006 Sep;62(3):345-57.
• [10] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [11] Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same? Drug Metab Dispos. 2005 Nov;33(11):1567-75.
• [12] In vitro inhibition of CYP1A2 by model inhibitors, anti-inflammatory analgesics and female sex steroids: predictability of in vivo interactions. Basic Clin Pharmacol Toxicol. 2008 Aug;103(2):157-65.
• [13] Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation. Pain. 2007 Jun;129(3):279-86.
• [14] Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Clin Pharmacol Ther. 2006 May;79(5):407-18.
• [15] Rofecoxib regulates the expression of genes related to the matrix metalloproteinase pathway in humans: implication for the adverse effects of cyclooxygenase-2 inhibitors. Clin Pharmacol Ther. 2006 Apr;79(4):303-15. doi: 10.1016/j.clpt.2005.12.306.
• [16] Molecular analysis of xenograft models of human cancer cachexia--possibilities for therapeutic intervention. Cancer Genomics Proteomics. 2007 May-Jun;4(3):223-31.
• [17] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [18] Analgesic action of acetaminophen in symptomatic osteoarthritis of the knee. Rheumatology (Oxford). 2006 Jun;45(6):765-70. doi: 10.1093/rheumatology/kei253. Epub 2006 Jan 31.
• [19] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [20] 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.