Details of the Drug Combination

General Information of Drug Combination (ID: DCUZKN5)

Drug Combination Name

Bardoxolone methyl Ibrutinib

Indication

Disease Entry	Status	REF
Diffuse large B cell lymphoma	Investigative	[1]

Component Drugs

Bardoxolone methyl DMODA2X

Ibrutinib DMHZCPO

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: TMD8

Zero Interaction Potency (ZIP) Score: 11.76

Bliss Independence Score: 10.66

Loewe Additivity Score: 10.02

LHighest Single Agent (HSA) Score: 12.68

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

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	[9]
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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	[10]
Alpha-2C adrenergic receptor (ADRA2C)	OT5B9RKP	ADA2C_HUMAN	Decreases Activity	[10]
D(1A) dopamine receptor (DRD1)	OTLZPBT7	DRD1_HUMAN	Decreases Activity	[10]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Decreases Activity	[10]
5-hydroxytryptamine receptor 2C (HTR2C)	OT6H8DE0	5HT2C_HUMAN	Decreases Activity	[10]
Alpha-1B adrenergic receptor (ADRA1B)	OTSAYAFD	ADA1B_HUMAN	Decreases Activity	[10]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Decreases Activity	[10]
Kappa-type opioid receptor (OPRK1)	OTXCZF4L	OPRK_HUMAN	Decreases Activity	[10]
3',5'-cyclic-AMP phosphodiesterase 4B (PDE4B)	OTOA8WU2	PDE4B_HUMAN	Decreases Activity	[10]
Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C)	OT6KFNMS	CAC1C_HUMAN	Decreases Activity	[10]
NF-kappa-B inhibitor epsilon (NFKBIE)	OTLAYEL9	IKBE_HUMAN	Increases Expression	[8]
Transcription factor MafG (MAFG)	OTBQFUZH	MAFG_HUMAN	Decreases Expression	[8]
SH3 domain-binding protein 5 (SH3BP5)	OTOOEGUJ	3BP5_HUMAN	Affects Expression	[11]
Dynamin-like 120 kDa protein, mitochondrial (OPA1)	OTJGNWPW	OPA1_HUMAN	Increases Cleavage	[12]
Mitofusin-2 (MFN2)	OTPYN8A3	MFN2_HUMAN	Decreases Expression	[12]
Annexin A1 (ANXA1)	OT5OFDJC	ANXA1_HUMAN	Affects Expression	[11]
Amino acid transporter heavy chain SLC3A2 (SLC3A2)	OTBR33M9	4F2_HUMAN	Decreases Expression	[8]
ATP-dependent 6-phosphofructokinase, muscle type (PFKM)	OT1QY9JM	PFKAM_HUMAN	Decreases Expression	[12]
Growth-regulated alpha protein (CXCL1)	OT3WCTZV	GROA_HUMAN	Increases Expression	[8]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[13]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[8]
Beta-1,4-galactosyltransferase 1 (B4GALT1)	OTBCXEK7	B4GT1_HUMAN	Increases Expression	[8]
Glutathione peroxidase 2 (GPX2)	OTXI2NTI	GPX2_HUMAN	Affects Expression	[11]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Increases Expression	[8]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Affects Expression	[11]
DnaJ homolog subfamily B member 1 (DNAJB1)	OTCOSEVH	DNJB1_HUMAN	Affects Expression	[11]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[8]
Lon protease homolog, mitochondrial (LONP1)	OT665WYT	LONM_HUMAN	Decreases Expression	[14]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Expression	[12]
Oxidized low-density lipoprotein receptor 1 (OLR1)	OTS44RIC	OLR1_HUMAN	Increases Expression	[8]
C-C motif chemokine 20 (CCL20)	OTUCJY4N	CCL20_HUMAN	Increases Expression	[8]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[15]
Tumor necrosis factor receptor superfamily member 9 (TNFRSF9)	OTNOM26L	TNR9_HUMAN	Increases Expression	[8]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Increases Expression	[8]
Kelch-like ECH-associated protein 1 (KEAP1)	OTFHOD0C	KEAP1_HUMAN	Decreases Expression	[8]
Neutral amino acid transporter B(0) (SLC1A5)	OTE2H26Q	AAAT_HUMAN	Decreases Expression	[12]
Mitofusin-1 (MFN1)	OTCBXQZF	MFN1_HUMAN	Decreases Expression	[12]
Thyroid hormone-inducible hepatic protein (THRSP)	OTKYE01L	THRSP_HUMAN	Decreases Expression	[16]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Increases Expression	[17]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[8]
Tribbles homolog 3 (TRIB3)	OTG5OS7X	TRIB3_HUMAN	Decreases Expression	[8]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Decreases Expression	[8]
Prolyl hydroxylase EGLN3 (EGLN3)	OTXV3RYX	EGLN3_HUMAN	Affects Expression	[11]
5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2)	OTHTAM54	AAKG2_HUMAN	Affects Expression	[8]
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⏷ Show the Full List of 44 DOT(s)

Indication(s) of Ibrutinib

Disease Entry	ICD 11	Status	REF
Mantle cell lymphoma	2A85.5	Approved	[4]
Small lymphocytic lymphoma	2A82.0	Approved	[5]
Waldenstrom macroglobulinemia	2A85.4	Approved	[5]
B-cell non-hodgkin lymphoma	2B33.5	Phase 3	[6]
Diffuse large B-cell lymphoma	2A81	Phase 3	[6]
Follicular lymphoma	2A80	Phase 3	[6]
Non-hodgkin lymphoma	2B33.5	Phase 3	[6]
Pancreatic cancer	2C10	Phase 3	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[7]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]

Ibrutinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase BTK (ATK)	TTGM6VW	BTK_HUMAN	Inhibitor	[18]
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Ibrutinib Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[19]
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Ibrutinib Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[20]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[20]
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Ibrutinib Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[21]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Decreases Expression	[21]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)	OTGVC9MY	PLCG2_HUMAN	Decreases Phosphorylation	[21]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Decreases Expression	[21]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Affects Localization	[21]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[21]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[21]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[22]
TNF receptor-associated factor 2 (TRAF2)	OT1MEZZN	TRAF2_HUMAN	Decreases Response To Substance	[21]
TNF receptor-associated factor 3 (TRAF3)	OT5TQBGV	TRAF3_HUMAN	Decreases Response To Substance	[21]
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14)	OTT3DOOL	M3K14_HUMAN	Decreases Response To Substance	[21]
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⏷ Show the Full List of 11 DOT(s)

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: 6912).
5	Ibrutinib FDA Label
6	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
7	Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization
8	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.
9	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.
10	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.
11	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.
12	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.
13	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.
14	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.
15	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.
16	Fatty acid synthesis is a therapeutic target in human liposarcoma. Int J Oncol. 2010 May;36(5):1309-14. doi: 10.3892/ijo_00000616.
17	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.
18	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: 1948).
19	P-Glycoprotein (MDR1/ABCB1) Restricts Brain Penetration of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib, While Cytochrome P450-3A (CYP3A) Limits Its Oral Bioavailability. Mol Pharm. 2018 Nov 5;15(11):5124-5134.
20	Absorption, metabolism, and excretion of oral 14C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men. Drug Metab Dispos. 2015 Feb;43(2):289-97.
21	Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.
22	Label-Free Bottom-Up Proteomic Workflow for Simultaneously Assessing the Target Specificity of Covalent Drug Candidates and Their Off-Target Reactivity to Selected Proteins. Chem Res Toxicol. 2016 Jan 19;29(1):109-16. doi: 10.1021/acs.chemrestox.5b00460. Epub 2015 Dec 29.