Details of the Drug Combination

General Information of Drug Combination (ID: DCB8YYZ)

• Drug Combination Name: Everolimus + Ibrutinib
• Indication: Diffuse large B cell lymphoma; Status: Investigative [1]
• Component Drugs:
  Everolimus (DM8X2EH): Small molecular drug
  Ibrutinib (DMHZCPO): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TMD8
  Zero Interaction Potency (ZIP) Score: 4.61
  Bliss Independence Score: 4.6
  Loewe Additivity Score: 23.29
  LHighest Single Agent (HSA) Score: 22.98

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Everolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Advanced/metastatic breast cancer	2C60	Approved	[3]
Brainstem neoplasm	N.A.	Approved	[2]
Breast carcinoma	N.A.	Approved	[2]
Graft-versus-host disease	4B24	Approved	[2]
Intracranial meningioma	N.A.	Approved	[2]
Leukemia	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Mucosal melanoma	N.A.	Approved	[2]
Multiple sclerosis	8A40	Approved	[2]
Plasma cell myeloma	2A83.1	Approved	[2]
Prostate cancer	2C82.0	Approved	[2]
Renal cell carcinoma	2C90	Approved	[4]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Tuberous sclerosis	LD2D.2	Approved	[2]
Kidney cancer	2C90.0	Phase 3	[4]
Castration-resistant prostate carcinoma	N.A.	Investigative	[2]
Colon cancer	2B90.Z	Investigative	[2]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[5]
Neuroblastoma	2D11.2	Investigative	[2]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[2]
Polycystic kidney disease	GB8Y	Investigative	[2]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[5]

Everolimus Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[10]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[5]

Everolimus 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]

Everolimus Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]

Indication(s) of Ibrutinib

Disease Entry	ICD 11	Status	REF
Mantle cell lymphoma	2A85.5	Approved	[6]
Small lymphocytic lymphoma	2A82.0	Approved	[7]
Waldenstrom macroglobulinemia	2A85.4	Approved	[7]
B-cell non-hodgkin lymphoma	2B33.5	Phase 3	[8]
Diffuse large B-cell lymphoma	2A81	Phase 3	[8]
Follicular lymphoma	2A80	Phase 3	[8]
Non-hodgkin lymphoma	2B33.5	Phase 3	[8]
Pancreatic cancer	2C10	Phase 3	[8]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[9]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[8]

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	[13]

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	[14]

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	[15]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]

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	[16]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[17]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Decreases Expression	[17]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[17]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)	OTGVC9MY	PLCG2_HUMAN	Decreases Phosphorylation	[17]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Decreases Expression	[17]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Expression	[17]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Decreases Expression	[17]
Polycomb complex protein BMI-1 (BMI1)	OTROVLJ0	BMI1_HUMAN	Decreases Expression	[17]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Affects Localization	[17]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[17]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[17]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Activity	[18]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[19]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[20]
Hemoglobin subunit beta (HBB)	OT514IKQ	HBB_HUMAN	Affects Binding	[19]
TNF receptor-associated factor 2 (TRAF2)	OT1MEZZN	TRAF2_HUMAN	Decreases Response To Substance	[17]
TNF receptor-associated factor 3 (TRAF3)	OT5TQBGV	TRAF3_HUMAN	Decreases Response To Substance	[17]
CREB-binding protein (CREBBP)	OTPA4QGM	CBP_HUMAN	Decreases Response To Substance	[17]
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14)	OTT3DOOL	M3K14_HUMAN	Decreases Response To Substance	[17]
Serine/threonine-protein kinase pim-1 (PIM1)	OTWEKXTU	PIM1_HUMAN	Decreases Response To Substance	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Metastatic Renal Cell Carcinoma	DCGNDH3	N. A.	Phase 1	[21]

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] Everolimus FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 5889).
• [5] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [6] 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).
• [7] Ibrutinib FDA Label
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization
• [10] Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma. Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9.
• [11] Closer to the Site of Action: Everolimus Concentrations in Peripheral Blood Mononuclear Cells Correlate Well With Whole Blood Concentrations. Ther Drug Monit. 2015 Oct;37(5):675-80.
• [12] The evolving experience using everolimus in clinical transplantation. Transplant Proc. 2004 Mar;36(2 Suppl):495S-499S.
• [13] 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).
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] ClinicalTrials.gov (NCT02599324) Study to Evaluate Ibrutinib Combination Therapy in Patients With Selected Gastrointestinal and Genitourinary Tumors