Details of the Drug Combination

General Information of Drug Combination (ID: DCB5XIH)

• Drug Combination Name: Dronedarone + Pomalidomide
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Dronedarone (DMA8FS5): Small molecular drug
  Pomalidomide (DMTGBAX): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 9.58
  Bliss Independence Score: 9.58
  Loewe Additivity Score: 24.59
  LHighest Single Agent (HSA) Score: 24.59

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dronedarone

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[2]
Atrial fibrillation	BC81.3	Withdrawn from market	[2]

Dronedarone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated potassium channel Kv1.5 (KCNA5)	TTW0CMT	KCNA5_HUMAN	Blocker	[5]
Potassium channel unspecific (KC)	TT1VOHK	NOUNIPROTAC	Inhibitor	[6]

Dronedarone Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[9]

Dronedarone Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Response To Substance	[10]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Response To Substance	[10]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Response To Substance	[10]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[11]
DNA topoisomerase 2-alpha (TOP2A)	OT6LPS08	TOP2A_HUMAN	Decreases Expression	[10]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[10]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[10]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[10]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Expression	[10]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[10]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[11]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[11]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Decreases Expression	[10]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[12]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[13]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Metabolism	[10]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Metabolism	[10]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Metabolism	[10]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Metabolism	[10]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Increases Metabolism	[10]
Cytochrome P450 2C18 (CYP2C18)	OTY687L9	CP2CI_HUMAN	Increases Metabolism	[10]

Indication(s) of Pomalidomide

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

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	[14]

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	[15]

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	[16]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[17]

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	[18]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Secretion	[19]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Secretion	[19]
Granulocyte colony-stimulating factor (CSF3)	OT9GC6TP	CSF3_HUMAN	Increases Secretion	[19]
Fibroblast growth factor receptor 1 (FGFR1)	OT4GLCXW	FGFR1_HUMAN	Decreases Expression	[20]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[19]
Erythroid transcription factor (GATA1)	OTX1R7O1	GATA1_HUMAN	Decreases Expression	[19]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Decreases Expression	[19]
Transcription factor PU.1 (SPI1)	OTVCA1D0	SPI1_HUMAN	Increases Expression	[19]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[19]
Fibroblast growth factor receptor 3 (FGFR3)	OTSAXDIL	FGFR3_HUMAN	Affects Expression	[20]
Endothelial transcription factor GATA-2 (GATA2)	OTBP2QQ2	GATA2_HUMAN	Decreases Expression	[19]
Rhombotin-2 (LMO2)	OTCC370G	RBTN2_HUMAN	Decreases Expression	[19]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Decreases Secretion	[19]
DNA-binding protein inhibitor ID-1 (ID1)	OTKGNZN5	ID1_HUMAN	Increases Expression	[19]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Increases Expression	[19]
CCAAT/enhancer-binding protein delta (CEBPD)	OTNBIPMY	CEBPD_HUMAN	Increases Expression	[19]
DNA-binding protein inhibitor ID-2 (ID2)	OT0U1D53	ID2_HUMAN	Increases Expression	[19]
Krueppel-like factor 1 (KLF1)	OT1FK08U	KLF1_HUMAN	Decreases Expression	[19]
CCAAT/enhancer-binding protein epsilon (CEBPE)	OTKZA25M	CEBPE_HUMAN	Increases Expression	[19]
Transcription factor NF-E2 45 kDa subunit (NFE2)	OTLM94BI	NFE2_HUMAN	Decreases Expression	[19]
Zinc finger protein Gfi-1b (GFI1B)	OTRDW8YO	GFI1B_HUMAN	Decreases Expression	[19]
Zinc finger protein Gfi-1 (GFI1)	OT9HB9H8	GFI1_HUMAN	Increases Expression	[19]
Sal-like protein 4 (SALL4)	OTC08PR5	SALL4_HUMAN	Affects Binding	[21]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Oxidation	[18]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Increases Oxidation	[18]
Protein cereblon (CRBN)	OTXH9MDC	CRBN_HUMAN	Increases Response To Substance	[22]

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: 7465).
• [3] Pomalidomide FDA Label
• [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: 7348).
• [5] New antiarrhythmic agents for atrial fibrillation and atrial flutter. Expert Opin Emerg Drugs. 2005 May;10(2):311-22.
• [6] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [7] Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf. 2012 Nov;11(6):1023-45.
• [8] Effect of dronedarone on the pharmacokinetics of carvedilol following oral administration to rats. Eur J Pharm Sci. 2018 Jan 1;111:13-19.
• [9] Inactivation of human cytochrome P450 3A4 and 3A5 by dronedarone and N-desbutyl dronedarone. Mol Pharmacol. 2016 Jan;89(1):1-13.
• [10] The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone. Arch Toxicol. 2018 Jun;92(6):1969-1981. doi: 10.1007/s00204-018-2196-x. Epub 2018 Apr 3.
• [11] Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone. Toxicol Sci. 2013 Feb;131(2):480-90. doi: 10.1093/toxsci/kfs298. Epub 2012 Nov 7.
• [12] Five novel single nucleotide polymorphisms in the CYP2C8 gene, one of which induces a frame-shift. Drug Metab Pharmacokinet. 2002;17(4):374-7. doi: 10.2133/dmpk.17.374.
• [13] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [14] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [15] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB08910)
• [16] 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.
• [17] Population pharmacokinetics of pomalidomide. J Clin Pharmacol. 2015 May;55(5):563-72.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.