Details of the Drug Combination

General Information of Drug Combination (ID: DC9T5EG)

• Drug Combination Name: Selumetinib + Carfilzomib
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Selumetinib (DMC7W6R): Small molecular drug
  Carfilzomib (DM48K0X): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 7.962
  Bliss Independence Score: 12.162
  Loewe Additivity Score: 2.781
  LHighest Single Agent (HSA) Score: 2.791

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Selumetinib

Disease Entry	ICD 11	Status	REF
Neurofibromatosis type 1	LD2D.10	Approved	[2]
Melanoma	2C30	Phase 3	[3]
Thyroid cancer	2D10	Phase 3	[4]
Non-small-cell lung cancer	2C25.Y	Phase 2	[5]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[6]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[6]
Solid tumour/cancer	2A00-2F9Z	Investigative	[7]

Selumetinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MAPK/ERK kinase kinase (MAP3K)	TTROQ37	NOUNIPROTAC	Modulator	[10]
ERK activator kinase 1 (MEK1)	TTIDAPM	MP2K1_HUMAN	Inhibitor	[4]
ERK activator kinase 2 (MEK2)	TTTW2NY	MP2K2_HUMAN	Inhibitor	[4]
HUMAN ERK activator kinase 1 (MEK1)	TTAW3TO	MP2K1_HUMAN	Inhibitor	[6]
HUMAN ERK activator kinase 2 (MEK2)	TTWX403	MP2K2_HUMAN	Inhibitor	[6]

Selumetinib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[11]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Decreases Phosphorylation	[12]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Activity	[12]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Activity	[12]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Activity	[12]
Cyclic AMP-responsive element-binding protein 1 (CREB1)	OT1MDLA1	CREB1_HUMAN	Decreases Phosphorylation	[12]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[13]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[13]

Indication(s) of Carfilzomib

Disease Entry	ICD 11	Status	REF
Multiple myeloma	2A83	Approved	[8]
Plasma cell myeloma	2A83.1	Approved	[9]
Small-cell lung cancer	2C25.Y	Phase 1/2	[4]

Carfilzomib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proteasome (PS)	TTU7ZMG	NOUNIPROTAC	Modulator	[15]

Carfilzomib Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[16]

Carfilzomib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[17]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[18]
Cytochrome c oxidase subunit 8A, mitochondrial (COX8A)	OTU0NR39	COX8A_HUMAN	Decreases Expression	[18]
Basigin (BSG)	OTD0CVEC	BASI_HUMAN	Decreases Expression	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[19]
C-X-C chemokine receptor type 4 (CXCR4)	OTUFSBX2	CXCR4_HUMAN	Decreases Expression	[19]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Activity	[18]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Increases Response To Substance	[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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] ClinicalTrials.gov (NCT01933932) Assess Efficacy & Safety of Selumetinib in Combination With Docetaxel in Patients Receiving 2nd Line Treatment for v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Positive NSCLC (SELECT-1)
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] 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: 5665).
• [6] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [7] 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. (Target id: 1479).
• [8] 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: 7420).
• [9] Carfilzomib FDA Label
• [10] Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.Br J Cancer.2012 May 8;106(10):1648-59.
• [11] Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther. 2012 Jul;11(7):1557-64. doi: 10.1158/1535-7163.MCT-11-0934. Epub 2012 Jun 22.
• [12] Ursonic acid exerts inhibitory effects on matrix metalloproteinases via ERK signaling pathway. Chem Biol Interact. 2020 Jan 5;315:108910. doi: 10.1016/j.cbi.2019.108910. Epub 2019 Nov 29.
• [13] The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition. Br J Cancer. 2012 Apr 10;106(8):1386-94. doi: 10.1038/bjc.2012.70. Epub 2012 Mar 13.
• [14] The Zinc-Finger AN1-Type Domain 2a Gene Acts as a Regulator of Cell Survival in Human Melanoma: Role of E3-Ligase cIAP2. Mol Cancer Res. 2019 Dec;17(12):2444-2456. doi: 10.1158/1541-7786.MCR-19-0243. Epub 2019 Sep 20.
• [15] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [16] Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1. Am J Hematol. 2013 Apr;88(4):265-72.
• [17] Identification and Profiling of Environmental Chemicals That Inhibit the TGF/SMAD Signaling Pathway. Chem Res Toxicol. 2019 Dec 16;32(12):2433-2444. doi: 10.1021/acs.chemrestox.9b00228. Epub 2019 Nov 11.
• [18] Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays. Molecules. 2019 Feb 27;24(5):841. doi: 10.3390/molecules24050841.
• [19] Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration. Oncotarget. 2016 Nov 22;7(47):77543-77557. doi: 10.18632/oncotarget.12721.
• [20] Suppression of BRCA1 sensitizes cells to proteasome inhibitors. Cell Death Dis. 2014 Dec 18;5(12):e1580. doi: 10.1038/cddis.2014.537.