Details of the Drug Combination

General Information of Drug Combination (ID: DCH7RY8)

• Drug Combination Name: IRX4204 + Marizomib
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  IRX4204 (DM9SCME): Small molecular drug
  Marizomib (DME9QGW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 4.41
  Bliss Independence Score: 3.08
  Loewe Additivity Score: 2.98
  LHighest Single Agent (HSA) Score: 3.09

Molecular Interaction Atlas of This Drug Combination

Indication(s) of IRX4204

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 1	[2]
Non-small-cell lung cancer	2C25.Y	Phase 1	[2]
Pancreatic cancer	2C10	Phase 1	[2]
Prostate cancer	2C82.0	Phase 1	[3]

IRX4204 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Retinoic acid receptor RXR-gamma (RXRG)	TTH029C	RXRG_HUMAN	Modulator	[7]
Retinoic acid receptor RXR (RXR)	TTP7WQM	NOUNIPROTAC	Agonist	[2]

IRX4204 Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[8]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[9]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[10]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[9]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Decreases Expression	[9]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[9]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[9]
Fos-related antigen 1 (FOSL1)	OT9YTYMB	FOSL1_HUMAN	Decreases Expression	[9]
Retinoic acid receptor RXR-alpha (RXRA)	OTP1TBDM	RXRA_HUMAN	Increases Activity	[11]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[10]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Expression	[9]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Expression	[9]
Mitogen-activated protein kinase 4 (MAPK4)	OTVWWUYS	MK04_HUMAN	Decreases Expression	[9]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[12]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Stability	[13]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[12]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Decreases Expression	[9]
Nuclear receptor coactivator 1 (NCOA1)	OTLIUJQD	NCOA1_HUMAN	Affects Response To Substance	[10]
CREB-binding protein (CREBBP)	OTPA4QGM	CBP_HUMAN	Affects Response To Substance	[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	[14]

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] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] ClinicalTrials.gov (NCT02438215) Study of IRX4204 for Treatment of Early Parkinson's Disease. U.S. National Institutes of Health.
• [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] Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease.Oncotarget.2016 Feb 16;7(7):7469-79.
• [8] Regulation of stearoyl coenzyme A desaturase expression in human retinal pigment epithelial cells by retinoic acid. J Biol Chem. 2001 Aug 3;276(31):28744-50. doi: 10.1074/jbc.M103587200. Epub 2001 Jun 7.
• [9] A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands. Breast Cancer Res. 2004;6(5):R546-55. doi: 10.1186/bcr913. Epub 2004 Jul 23.
• [10] Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands. BMC Cancer. 2010 Nov 16;10:629. doi: 10.1186/1471-2407-10-629.
• [11] The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPAR in Xenopus tropicalis. Toxicol Appl Pharmacol. 2017 Jan 1;314:91-97. doi: 10.1016/j.taap.2016.11.014. Epub 2016 Nov 25.
• [12] Combination therapy of insulin-like growth factor binding protein-3 and retinoid X receptor ligands synergize on prostate cancer cell apoptosis in vitro and in vivo. Clin Cancer Res. 2005 Jul 1;11(13):4851-6. doi: 10.1158/1078-0432.CCR-04-2160.
• [13] Retinoids inhibit proliferation of human coronary smooth muscle cells by modulating cell cycle regulators. Arterioscler Thromb Vasc Biol. 2001 May;21(5):746-51. doi: 10.1161/01.atv.21.5.746.
• [14] 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.