Details of the Drug Combination

General Information of Drug Combination (ID: DCSSOK3)

• Drug Combination Name: Pomalidomide + Bepridil
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pomalidomide (DMTGBAX): Small molecular drug
  Bepridil (DM0RKS4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 0.83
  Bliss Independence Score: 0.83
  Loewe Additivity Score: 15.63
  LHighest Single Agent (HSA) Score: 15.63

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pomalidomide

Disease Entry	ICD 11	Status	REF
Plasma cell myeloma	2A83.1	Approved	[2]
Systemic sclerosis	4A42	Approved	[3]

Pomalidomide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiogenesis/myeloma cell growth (AMCG)	TTDIBYJ	NOUNIPROTAC	Modulator	[5]

Pomalidomide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Pomalidomide Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[8]

Pomalidomide Interacts with 27 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Oxidation	[9]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Secretion	[10]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Secretion	[10]
Granulocyte colony-stimulating factor (CSF3)	OT9GC6TP	CSF3_HUMAN	Increases Secretion	[10]
Fibroblast growth factor receptor 1 (FGFR1)	OT4GLCXW	FGFR1_HUMAN	Decreases Expression	[11]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[10]
Erythroid transcription factor (GATA1)	OTX1R7O1	GATA1_HUMAN	Decreases Expression	[10]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Decreases Expression	[10]
Transcription factor PU.1 (SPI1)	OTVCA1D0	SPI1_HUMAN	Increases Expression	[10]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[10]
Fibroblast growth factor receptor 3 (FGFR3)	OTSAXDIL	FGFR3_HUMAN	Affects Expression	[11]
Endothelial transcription factor GATA-2 (GATA2)	OTBP2QQ2	GATA2_HUMAN	Decreases Expression	[10]
Rhombotin-2 (LMO2)	OTCC370G	RBTN2_HUMAN	Decreases Expression	[10]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Decreases Secretion	[10]
DNA-binding protein inhibitor ID-1 (ID1)	OTKGNZN5	ID1_HUMAN	Increases Expression	[10]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Increases Expression	[10]
CCAAT/enhancer-binding protein delta (CEBPD)	OTNBIPMY	CEBPD_HUMAN	Increases Expression	[10]
DNA-binding protein inhibitor ID-2 (ID2)	OT0U1D53	ID2_HUMAN	Increases Expression	[10]
Krueppel-like factor 1 (KLF1)	OT1FK08U	KLF1_HUMAN	Decreases Expression	[10]
CCAAT/enhancer-binding protein epsilon (CEBPE)	OTKZA25M	CEBPE_HUMAN	Increases Expression	[10]
Transcription factor NF-E2 45 kDa subunit (NFE2)	OTLM94BI	NFE2_HUMAN	Decreases Expression	[10]
Zinc finger protein Gfi-1b (GFI1B)	OTRDW8YO	GFI1B_HUMAN	Decreases Expression	[10]
Zinc finger protein Gfi-1 (GFI1)	OT9HB9H8	GFI1_HUMAN	Increases Expression	[10]
Sal-like protein 4 (SALL4)	OTC08PR5	SALL4_HUMAN	Affects Binding	[12]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Oxidation	[9]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Increases Oxidation	[9]
Protein cereblon (CRBN)	OTXH9MDC	CRBN_HUMAN	Increases Response To Substance	[13]

Indication(s) of Bepridil

Disease Entry	ICD 11	Status	REF
Chronic/stable angina	BA40.1	Approved	[4]

Bepridil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Calcium channel unspecific (CaC)	TT5HONZ	NOUNIPROTAC	Modulator	[14]

Bepridil Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[15]

Bepridil Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[17]

Bepridil Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[18]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[18]
Potassium voltage-gated channel subfamily A member 5 (KCNA5)	OTHI2N71	KCNA5_HUMAN	Decreases Activity	[19]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[18]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Response To Substance	[18]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[20]
Eukaryotic translation initiation factor 2A (EIF2A)	OTWXELQP	EIF2A_HUMAN	Increases Phosphorylation	[18]

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] Pomalidomide FDA Label
• [3] 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: 7348).
• [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: 2337).
• [5] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [6] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB08910)
• [7] Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects. J Clin Pharmacol. 2015 Feb;55(2):168-78.
• [8] Population pharmacokinetics of pomalidomide. J Clin Pharmacol. 2015 May;55(5):563-72.
• [9] Human cytochrome P450 oxidation of 5-hydroxythalidomide and pomalidomide, an amino analogue of thalidomide. Chem Res Toxicol. 2014 Jan 21;27(1):147-56. doi: 10.1021/tx4004215. Epub 2013 Dec 24.
• [10] Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood. 2005 May 15;105(10):3833-40. doi: 10.1182/blood-2004-03-0828. Epub 2004 Aug 3.
• [11] Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR Gene Expression while Pomalidomide Dampens FGFR2 Activity. Chem Res Toxicol. 2019 Apr 15;32(4):589-602. doi: 10.1021/acs.chemrestox.8b00286. Epub 2019 Mar 15.
• [12] Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife. 2018 Aug 1;7:e38430. doi: 10.7554/eLife.38430.
• [13] A Dual Color Immunohistochemistry Assay for Measurement of Cereblon in Multiple Myeloma Patient Samples. Appl Immunohistochem Mol Morphol. 2016 Nov/Dec;24(10):695-702. doi: 10.1097/PAI.0000000000000246.
• [14] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [15] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [16] Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17.
• [17] Serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity. Drug Metab Pharmacokinet. 2015 Aug;30(4):257-62.
• [18] Amiodarone sensitizes human glioma cells but not astrocytes to TRAIL-induced apoptosis via CHOP-mediated DR5 upregulation. Neuro Oncol. 2011 Mar;13(3):267-79. doi: 10.1093/neuonc/noq195. Epub 2011 Feb 3.
• [19] Inhibitory effect of bepridil on hKv1.5 channel current: comparison with amiodarone and E-4031. Eur J Pharmacol. 2001 Nov 2;430(2-3):149-57. doi: 10.1016/s0014-2999(01)01381-4.
• [20] Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds. Assay Drug Dev Technol. 2004 Oct;2(5):497-506. doi: 10.1089/adt.2004.2.497.