Details of the Drug Combination

General Information of Drug Combination (ID: DCMSI3U)

• Drug Combination Name: Ruxolitinib + Ibrutinib
• Indication: Steroid Refractory GVHD; Status: Phase 1 [1]
• Component Drugs:
  Ruxolitinib (DM7Q98D): Small molecular drug
  Ibrutinib (DMHZCPO): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[2]
High-risk myelofibrosis	2A20.2	Approved	[3]
Myelofibrosis	2A22	Approved	[4]
Myeloproliferative neoplasm	2A20	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Pancreatic cancer	2C10	Phase 3	[3]
Atopic dermatitis	EA80	Phase 1/2	[7]
Vitiligo	ED63.0	Phase 1/2	[7]

Ruxolitinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Janus kinase 2 (JAK-2)	TTRMX3V	JAK2_HUMAN	Modulator	[12]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[12]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[13]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[14]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[14]

Ruxolitinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Mitogen-activated protein kinase 14 (MAPK14)	OT5TCO3O	MK14_HUMAN	Increases ADR	[15]

Indication(s) of Ibrutinib

Disease Entry	ICD 11	Status	REF
Mantle cell lymphoma	2A85.5	Approved	[8]
Small lymphocytic lymphoma	2A82.0	Approved	[9]
Waldenstrom macroglobulinemia	2A85.4	Approved	[9]
B-cell non-hodgkin lymphoma	2B33.5	Phase 3	[10]
Diffuse large B-cell lymphoma	2A81	Phase 3	[10]
Follicular lymphoma	2A80	Phase 3	[10]
Non-hodgkin lymphoma	2B33.5	Phase 3	[10]
Pancreatic cancer	2C10	Phase 3	[10]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[11]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[10]

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	[16]

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	[17]

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	[18]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[18]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[18]

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	[19]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[20]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Decreases Expression	[20]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[20]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)	OTGVC9MY	PLCG2_HUMAN	Decreases Phosphorylation	[20]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Decreases Expression	[20]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Expression	[20]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Decreases Expression	[20]
Polycomb complex protein BMI-1 (BMI1)	OTROVLJ0	BMI1_HUMAN	Decreases Expression	[20]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Affects Localization	[20]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[20]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[20]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Activity	[21]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[22]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[23]
Hemoglobin subunit beta (HBB)	OT514IKQ	HBB_HUMAN	Affects Binding	[22]
TNF receptor-associated factor 2 (TRAF2)	OT1MEZZN	TRAF2_HUMAN	Decreases Response To Substance	[20]
TNF receptor-associated factor 3 (TRAF3)	OT5TQBGV	TRAF3_HUMAN	Decreases Response To Substance	[20]
CREB-binding protein (CREBBP)	OTPA4QGM	CBP_HUMAN	Decreases Response To Substance	[20]
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14)	OTT3DOOL	M3K14_HUMAN	Decreases Response To Substance	[20]
Serine/threonine-protein kinase pim-1 (PIM1)	OTWEKXTU	PIM1_HUMAN	Decreases Response To Substance	[20]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Leukemia, Lymphocytic, Chronic, B-Cell	DCMBQ7F	N. A.	Phase 1	[24]

References

• [1] ClinicalTrials.gov (NCT05052385) ECP Combination Study
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] 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: 5688).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Ruxolitinib FDA Label
• [6] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] 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).
• [9] Ibrutinib FDA Label
• [10] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [11] Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization
• [12] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [13] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [14] The Use of Anti-Inflammatory Drugs in the Treatment of People With Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists From China. Clin Immunol. 2020 May;214:108393.
• [15] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [16] 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).
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [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.
• [23] 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.
• [24] ClinicalTrials.gov (NCT02912754) Ruxolitinib Combined With Ibrutinib in Chronic Lymphocytic Leukemia Patients