Details of the Drug Combination

General Information of Drug Combination (ID: DCZHSVE)

• Drug Combination Name: Midostaurin + Ibrutinib
• Indication: Diffuse large B cell lymphoma; Status: Investigative [1]
• Component Drugs:
  Midostaurin (DMI6E0R): Small molecular drug
  Ibrutinib (DMHZCPO): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TMD8
  Zero Interaction Potency (ZIP) Score: 8.03
  Bliss Independence Score: 7.34
  Loewe Additivity Score: 3.71
  LHighest Single Agent (HSA) Score: 5.61

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Midostaurin

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Approved	[2]
Systemic mastocytosis	2A21.0	Approved	[3]
Chronic myelomonocytic leukaemia	2A40	Phase 2	[4]
Colorectal cancer	2B91.Z	Phase 1	[4]

Midostaurin Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Protein kinase C gamma (PRKCG)	TTRFOXJ	KPCG_HUMAN	Inhibitor	[9]
Fms-like tyrosine kinase 3 (FLT-3)	TTGJCWZ	FLT3_HUMAN	Inhibitor	[9]

Midostaurin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

Midostaurin Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]

Midostaurin Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[12]
Receptor-type tyrosine-protein kinase FLT3 (FLT3)	OTMSRYMK	FLT3_HUMAN	Decreases Response To Substance	[13]
Glycophorin-A (GYPA)	OTABU4YV	GLPA_HUMAN	Decreases Expression	[14]
Fibroblast growth factor receptor 3 (FGFR3)	OTSAXDIL	FGFR3_HUMAN	Decreases Activity	[15]
Thrombopoietin receptor (MPL)	OTZEN192	TPOR_HUMAN	Increases Expression	[14]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[16]

Indication(s) of Ibrutinib

Disease Entry	ICD 11	Status	REF
Mantle cell lymphoma	2A85.5	Approved	[5]
Small lymphocytic lymphoma	2A82.0	Approved	[6]
Waldenstrom macroglobulinemia	2A85.4	Approved	[6]
B-cell non-hodgkin lymphoma	2B33.5	Phase 3	[7]
Diffuse large B-cell lymphoma	2A81	Phase 3	[7]
Follicular lymphoma	2A80	Phase 3	[7]
Non-hodgkin lymphoma	2B33.5	Phase 3	[7]
Pancreatic cancer	2C10	Phase 3	[7]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[8]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[7]

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	[17]

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	[18]

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	[19]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[19]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[19]

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	[20]
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]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_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]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Expression	[21]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Decreases Expression	[21]
Polycomb complex protein BMI-1 (BMI1)	OTROVLJ0	BMI1_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]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Activity	[22]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[23]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[24]
Hemoglobin subunit beta (HBB)	OT514IKQ	HBB_HUMAN	Affects Binding	[23]
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]
CREB-binding protein (CREBBP)	OTPA4QGM	CBP_HUMAN	Decreases Response To Substance	[21]
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14)	OTT3DOOL	M3K14_HUMAN	Decreases Response To Substance	[21]
Serine/threonine-protein kinase pim-1 (PIM1)	OTWEKXTU	PIM1_HUMAN	Decreases Response To Substance	[21]

References

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• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2018
• [3] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [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: 5702).
• [5] 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).
• [6] Ibrutinib FDA Label
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization
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• [11] Midostaurin, a novel protein kinase inhibitor for the treatment of acute myelogenous leukemia: insights from human absorption, metabolism, and excretion studies of a BDDCS II drug. Drug Metab Dispos. 2017 May;45(5):540-555.
• [12] Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica. 2002 Feb;87(2):167-76.
• [13] Reversible resistance induced by FLT3 inhibition: a novel resistance mechanism in mutant FLT3-expressing cells. PLoS One. 2011;6(9):e25351. doi: 10.1371/journal.pone.0025351. Epub 2011 Sep 28.
• [14] Oral small-molecule tyrosine kinase inhibitor midostaurin (PKC412) inhibits growth and induces megakaryocytic differentiation in human leukemia cells. Toxicol In Vitro. 2009 Sep;23(6):979-85. doi: 10.1016/j.tiv.2009.06.027. Epub 2009 Jun 30.
• [15] FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. Oncogene. 2005 Dec 15;24(56):8259-67. doi: 10.1038/sj.onc.1208989.
• [16] Selective inhibition of aldo-keto reductase 1C3: a novel mechanism involved in midostaurin and daunorubicin synergism. Arch Toxicol. 2021 Jan;95(1):67-78. doi: 10.1007/s00204-020-02884-2. Epub 2020 Oct 6.
• [17] 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).
• [18] 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.
• [19] 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.
• [20] 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.
• [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] 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.
• [23] 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.
• [24] 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.