Details of the Drug Combination

General Information of Drug Combination (ID: DCOC2X4)

• Drug Combination Name: Bardoxolone methyl + Romidepsin
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  Bardoxolone methyl (DMODA2X): Small molecular drug
  Romidepsin (DMT5GNL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 6.057
  Bliss Independence Score: 4.758
  Loewe Additivity Score: 1.904
  LHighest Single Agent (HSA) Score: 5.297

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bardoxolone methyl

Disease Entry	ICD 11	Status	REF
Mixed connective tissue disease	4A43.3	Phase 3	[2]
Pulmonary arterial hypertension	BB01.0	Phase 2	[3]
Pulmonary hypertension	BB01	Phase 2	[2]

Bardoxolone methyl Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
PPAR-gamma messenger RNA (PPARG mRNA)	TTT2SVW	PPARG_HUMAN	Antagonist	[8]

Bardoxolone methyl Interacts with 44 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Decreases Activity	[9]
Alpha-2C adrenergic receptor (ADRA2C)	OT5B9RKP	ADA2C_HUMAN	Decreases Activity	[9]
D(1A) dopamine receptor (DRD1)	OTLZPBT7	DRD1_HUMAN	Decreases Activity	[9]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Decreases Activity	[9]
5-hydroxytryptamine receptor 2C (HTR2C)	OT6H8DE0	5HT2C_HUMAN	Decreases Activity	[9]
Alpha-1B adrenergic receptor (ADRA1B)	OTSAYAFD	ADA1B_HUMAN	Decreases Activity	[9]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Decreases Activity	[9]
Kappa-type opioid receptor (OPRK1)	OTXCZF4L	OPRK_HUMAN	Decreases Activity	[9]
3',5'-cyclic-AMP phosphodiesterase 4B (PDE4B)	OTOA8WU2	PDE4B_HUMAN	Decreases Activity	[9]
Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C)	OT6KFNMS	CAC1C_HUMAN	Decreases Activity	[9]
NF-kappa-B inhibitor epsilon (NFKBIE)	OTLAYEL9	IKBE_HUMAN	Increases Expression	[7]
Transcription factor MafG (MAFG)	OTBQFUZH	MAFG_HUMAN	Decreases Expression	[7]
SH3 domain-binding protein 5 (SH3BP5)	OTOOEGUJ	3BP5_HUMAN	Affects Expression	[10]
Dynamin-like 120 kDa protein, mitochondrial (OPA1)	OTJGNWPW	OPA1_HUMAN	Increases Cleavage	[11]
Mitofusin-2 (MFN2)	OTPYN8A3	MFN2_HUMAN	Decreases Expression	[11]
Annexin A1 (ANXA1)	OT5OFDJC	ANXA1_HUMAN	Affects Expression	[10]
Amino acid transporter heavy chain SLC3A2 (SLC3A2)	OTBR33M9	4F2_HUMAN	Decreases Expression	[7]
ATP-dependent 6-phosphofructokinase, muscle type (PFKM)	OT1QY9JM	PFKAM_HUMAN	Decreases Expression	[11]
Growth-regulated alpha protein (CXCL1)	OT3WCTZV	GROA_HUMAN	Increases Expression	[7]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[12]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[7]
Beta-1,4-galactosyltransferase 1 (B4GALT1)	OTBCXEK7	B4GT1_HUMAN	Increases Expression	[7]
Glutathione peroxidase 2 (GPX2)	OTXI2NTI	GPX2_HUMAN	Affects Expression	[10]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Increases Expression	[7]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Affects Expression	[10]
DnaJ homolog subfamily B member 1 (DNAJB1)	OTCOSEVH	DNJB1_HUMAN	Affects Expression	[10]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[7]
Lon protease homolog, mitochondrial (LONP1)	OT665WYT	LONM_HUMAN	Decreases Expression	[13]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Expression	[11]
Oxidized low-density lipoprotein receptor 1 (OLR1)	OTS44RIC	OLR1_HUMAN	Increases Expression	[7]
C-C motif chemokine 20 (CCL20)	OTUCJY4N	CCL20_HUMAN	Increases Expression	[7]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[14]
Tumor necrosis factor receptor superfamily member 9 (TNFRSF9)	OTNOM26L	TNR9_HUMAN	Increases Expression	[7]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Increases Expression	[7]
Kelch-like ECH-associated protein 1 (KEAP1)	OTFHOD0C	KEAP1_HUMAN	Decreases Expression	[7]
Neutral amino acid transporter B(0) (SLC1A5)	OTE2H26Q	AAAT_HUMAN	Decreases Expression	[11]
Mitofusin-1 (MFN1)	OTCBXQZF	MFN1_HUMAN	Decreases Expression	[11]
Thyroid hormone-inducible hepatic protein (THRSP)	OTKYE01L	THRSP_HUMAN	Decreases Expression	[15]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Increases Expression	[16]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[7]
Tribbles homolog 3 (TRIB3)	OTG5OS7X	TRIB3_HUMAN	Decreases Expression	[7]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Decreases Expression	[7]
Prolyl hydroxylase EGLN3 (EGLN3)	OTXV3RYX	EGLN3_HUMAN	Affects Expression	[10]
5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2)	OTHTAM54	AAKG2_HUMAN	Affects Expression	[7]

Indication(s) of Romidepsin

Disease Entry	ICD 11	Status	REF
Cutaneous T-cell lymphoma	2B01	Approved	[4]
Gastrin-producing neuroendocrine tumor	N.A.	Approved	[5]
Glucagonoma	N.A.	Approved	[5]
Insulinoma	2C10.1	Approved	[5]
Lung carcinoid tumor	N.A.	Approved	[5]
Melanoma	2C30	Approved	[5]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[5]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[5]
Urethral cancer	2C93	Approved	[5]
Peripheral T-cell lymphoma	2A90.C	Phase 3	[6]
Renal cell carcinoma	2C90	Phase 3	[4]

Romidepsin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histone deacetylase 1 (HDAC1)	TT6R7JZ	HDAC1_HUMAN	Inhibitor	[19]

Romidepsin Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[20]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[20]

Romidepsin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[21]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[22]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[23]

Romidepsin Interacts with 27 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[24]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Expression	[25]
E3 SUMO-protein ligase CBX4 (CBX4)	OT4XVRRF	CBX4_HUMAN	Increases Expression	[26]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[27]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[28]
Growth arrest and DNA damage-inducible protein GADD45 beta (GADD45B)	OTL9I7LO	GA45B_HUMAN	Increases Expression	[29]
Serine/threonine-protein kinase 17B (STK17B)	OT4NYNO8	ST17B_HUMAN	Increases Expression	[26]
RAF proto-oncogene serine/threonine-protein kinase (RAF1)	OT51LSFO	RAF1_HUMAN	Decreases Expression	[30]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Expression	[30]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[30]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[31]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[18]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[26]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Expression	[31]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[18]
Receptor-type tyrosine-protein kinase FLT3 (FLT3)	OTMSRYMK	FLT3_HUMAN	Decreases Phosphorylation	[18]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[32]
Friend leukemia integration 1 transcription factor (FLI1)	OT0EV3LX	FLI1_HUMAN	Decreases Expression	[33]
RNA-binding protein EWS (EWSR1)	OT7SRHV3	EWS_HUMAN	Decreases Expression	[33]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[26]
Spectrin alpha chain, non-erythrocytic 1 (SPTAN1)	OT6VY3A3	SPTN1_HUMAN	Increases Expression	[26]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Expression	[34]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[35]
Histone H3.1t (H3-4)	OTY6ITYF	H31T_HUMAN	Increases Acetylation	[34]
Mitogen-activated protein kinase kinase kinase 3 (MAP3K3)	OT53LJGW	M3K3_HUMAN	Increases Expression	[26]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Response To Substance	[31]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 7006).
• [5] Romidepsin FDA Label
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Mapping the dynamics of Nrf2 antioxidant and NFB inflammatory responses by soft electrophilic chemicals in human liver cells defines the transition from adaptive to adverse responses. Toxicol In Vitro. 2022 Oct;84:105419. doi: 10.1016/j.tiv.2022.105419. Epub 2022 Jun 17.
• [8] A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor gamma. Mol Endocrinol. 2000 Oct;14(10):1550-6.
• [9] Characterization of the potent, selective Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one, in cellular and in vivo models of pulmonary oxidative stress. J Pharmacol Exp Ther. 2017 Oct;363(1):114-125.
• [10] Fluorescent tagging of endogenous Heme oxygenase-1 in human induced pluripotent stem cells for high content imaging of oxidative stress in various differentiated lineages. Arch Toxicol. 2021 Oct;95(10):3285-3302. doi: 10.1007/s00204-021-03127-8. Epub 2021 Sep 4.
• [11] Synthetic oleanane triterpenoid derivative CDDO-Me disrupts cellular bioenergetics to suppress pancreatic ductal adenocarcinoma via targeting SLC1A5. J Biochem Mol Toxicol. 2022 Nov;36(11):e23192. doi: 10.1002/jbt.23192. Epub 2022 Aug 5.
• [12] The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res. 2007 Mar 15;67(6):2414-9. doi: 10.1158/0008-5472.CAN-06-4534.
• [13] Lonp1 and Sig-1R contribute to the counteraction of ursolic acid against ochratoxin A-induced mitochondrial apoptosis. Food Chem Toxicol. 2023 Feb;172:113592. doi: 10.1016/j.fct.2022.113592. Epub 2022 Dec 29.
• [14] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [15] Fatty acid synthesis is a therapeutic target in human liposarcoma. Int J Oncol. 2010 May;36(5):1309-14. doi: 10.3892/ijo_00000616.
• [16] Bardoxolone methyl modulates efflux transporter and detoxifying enzyme expression in cisplatin-induced kidney cell injury. Toxicol Lett. 2016 Sep 30;259:52-59. doi: 10.1016/j.toxlet.2016.07.021. Epub 2016 Jul 29.
• [17] Inhibition of transcription, expression, and secretion of the vascular epithelial growth factor in human epithelial endometriotic cells by romidepsin. Fertil Steril. 2011 Apr;95(5):1579-83. doi: 10.1016/j.fertnstert.2010.12.058. Epub 2011 Feb 4.
• [18] Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3. Arch Toxicol. 2022 Jan;96(1):177-193. doi: 10.1007/s00204-021-03174-1. Epub 2021 Oct 19.
• [19] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [20] Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009 Feb 15;15(4):1496-503.
• [21] A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03. Neuro Oncol. 2011 May;13(5):509-16.
• [22] Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009 Feb 15;15(4):1496-503.
• [23] FDA Label of Romidepsin. The 2020 official website of the U.S. Food and Drug Administration.
• [24] Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines. J Pharmacol Exp Ther. 2005 Jul;314(1):467-75. doi: 10.1124/jpet.105.083956. Epub 2005 Apr 15.
• [25] Aberrant promoter methylation of the ABCG2 gene in renal carcinoma. Mol Cell Biol. 2006 Nov;26(22):8572-85.
• [26] 5-Aza-2'-deoxycytidine and depsipeptide synergistically induce expression of BIK (BCL2-interacting killer). Biochem Biophys Res Commun. 2006 Dec 15;351(2):455-61. doi: 10.1016/j.bbrc.2006.10.055. Epub 2006 Oct 18.
• [27] Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res. 2006 Jul 15;66(14):7317-25. doi: 10.1158/0008-5472.CAN-06-0680.
• [28] Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells. Int J Cancer. 2004 Jun 10;110(2):301-8. doi: 10.1002/ijc.20117.
• [29] A sequential treatment of depsipeptide followed by 5-azacytidine enhances Gadd45beta expression in hepatocellular carcinoma cells. Anticancer Res. 2007 Nov-Dec;27(6B):3783-9.
• [30] Abrogation of p21 expression by flavopiridol enhances depsipeptide-mediated apoptosis in malignant pleural mesothelioma cells. Clin Cancer Res. 2004 Mar 1;10(5):1813-25. doi: 10.1158/1078-0432.ccr-0901-3.
• [31] Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res. 2008 Jan 15;14(2):549-58. doi: 10.1158/1078-0432.CCR-07-1934.
• [32] Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells. Blood. 2006 Feb 15;107(4):1546-54. doi: 10.1182/blood-2004-10-4126. Epub 2005 Oct 13.
• [33] Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors. Int J Cancer. 2005 Sep 20;116(5):784-92. doi: 10.1002/ijc.21069.
• [34] Enhanced transgene expression in urothelial cancer gene therapy with histone deacetylase inhibitor. J Urol. 2005 Aug;174(2):747-52. doi: 10.1097/01.ju.0000164723.20555.e6.
• [35] Blocking downstream signaling pathways in the context of HDAC inhibition promotes apoptosis preferentially in cells harboring mutant Ras. Oncotarget. 2016 Oct 25;7(43):69804-69815. doi: 10.18632/oncotarget.12001.