Details of the Drug Combination

General Information of Drug Combination (ID: DCU9N9T)

Drug Combination Name

Abexinostat Ibrutinib

Indication

Disease Entry	Status	REF
Diffuse Large B-cell Lymphoma	Phase 1	[1]

Component Drugs

Abexinostat DM91LGU

Ibrutinib DMHZCPO

Small molecular drug

2D MOL

3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of Abexinostat

Disease Entry	ICD 11	Status	REF
Follicular lymphoma	2A80	Phase 3	[2]
Renal cell carcinoma	2C90	Phase 3	[3]
Acute myeloid leukaemia	2A60	Phase 2	[2]
Breast cancer	2C60-2C65	Phase 2	[2]
Diffuse large B-cell lymphoma	2A81	Phase 2	[2]
Gynecologic cancer	2F33-2F76	Phase 2	[2]
Peripheral T-cell lymphoma	2A90.C	Phase 2	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[2]

Abexinostat Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histone deacetylase (HDAC)	TTBH0VX	NOUNIPROTAC	Modulator	[8]
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Abexinostat Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Expression	[7]
Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G)	OT8V1J4M	GA45G_HUMAN	Increases Expression	[9]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[7]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[7]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[9]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Decreases Expression	[7]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[7]
Heme oxygenase 2 (HMOX2)	OTG40XBT	HMOX2_HUMAN	Decreases Expression	[7]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[7]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[9]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[7]
C-C motif chemokine 7 (CCL7)	OTDIS99H	CCL7_HUMAN	Decreases Expression	[7]
Transcription factor RelB (RELB)	OTU3QYEF	RELB_HUMAN	Decreases Expression	[7]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[9]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[7]
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⏷ Show the Full List of 15 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	[2]
Diffuse large B-cell lymphoma	2A81	Phase 3	[2]
Follicular lymphoma	2A80	Phase 3	[2]
Non-hodgkin lymphoma	2B33.5	Phase 3	[2]
Pancreatic cancer	2C10	Phase 3	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[6]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[2]

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	[10]
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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	[11]
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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	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
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Ibrutinib Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase BTK (BTK)	OTG3CDVK	BTK_HUMAN	Decreases Response To Substance	[13]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[14]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Decreases Expression	[14]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[14]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)	OTGVC9MY	PLCG2_HUMAN	Decreases Phosphorylation	[14]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Decreases Expression	[14]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Expression	[14]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Decreases Expression	[14]
Polycomb complex protein BMI-1 (BMI1)	OTROVLJ0	BMI1_HUMAN	Decreases Expression	[14]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Affects Localization	[14]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[14]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[14]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Activity	[15]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[16]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[17]
Hemoglobin subunit beta (HBB)	OT514IKQ	HBB_HUMAN	Affects Binding	[16]
TNF receptor-associated factor 2 (TRAF2)	OT1MEZZN	TRAF2_HUMAN	Decreases Response To Substance	[14]
TNF receptor-associated factor 3 (TRAF3)	OT5TQBGV	TRAF3_HUMAN	Decreases Response To Substance	[14]
CREB-binding protein (CREBBP)	OTPA4QGM	CBP_HUMAN	Decreases Response To Substance	[14]
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14)	OTT3DOOL	M3K14_HUMAN	Decreases Response To Substance	[14]
Serine/threonine-protein kinase pim-1 (PIM1)	OTWEKXTU	PIM1_HUMAN	Decreases Response To Substance	[14]
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⏷ Show the Full List of 21 DOT(s)

References

1	ClinicalTrials.gov (NCT03939182) Abexinostat and Ibrutinib in Diffuse Large B-cell Lymphoma and Mantle Cell Lymphoma
2	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
3	ClinicalTrials.gov (NCT03592472) A Study of Pazopanib With or Without Abexinostat in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma (RENAVIV). U.S. National Institutes of Health.
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	Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization
7	PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells. Clin Cancer Res. 2009 May 15;15(10):3354-65. doi: 10.1158/1078-0432.CCR-08-2365. Epub 2009 May 5.
8	Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia. Invest New Drugs. 2015 Apr;33(2):423-31.
9	HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19482-7. doi: 10.1073/pnas.0707828104. Epub 2007 Nov 27.
10	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).
11	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.
12	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.
13	Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia. 2015 Apr;29(4):895-900. doi: 10.1038/leu.2014.263. Epub 2014 Sep 5.
14	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.
15	Blockade of oncogenic IB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors. Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11365-70. doi: 10.1073/pnas.1411701111. Epub 2014 Jul 21.
16	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.
17	Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.