Details of the Drug Combination

General Information of Drug Combination (ID: DC6U9X7)

• Drug Combination Name: Napabucasin + Ibrutinib
• Indication: Hematologic Malignancy; Status: Phase 1 [1]
• Component Drugs:
  Napabucasin (DMDZ6Q3): N.A.
  Ibrutinib (DMHZCPO): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Napabucasin

Disease Entry	ICD 11	Status	REF
Colorectal cancer	2B91.Z	Phase 3	[2]
Pancreatic cancer	2C10	Phase 3	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 3	[3]
Advanced malignancy	2A00-2F9Z	Phase 1/2	[2]
Gastrointestinal cancer	2C11	Phase 1/2	[2]
Hepatocellular carcinoma	2C12.02	Phase 1/2	[2]
Recurrent glioblastoma	2A00.00	Phase 1/2	[4]
Recurring respiratory infection	CA07-CA45	Phase 1/2	[2]
Haematological malignancy	2B33.Y	Phase 1	[2]

Napabucasin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Signal transducer and activator of transcription 3 (STAT3)	TTH8FZW	STAT3_HUMAN	Inhibitor	[2]

Napabucasin Interacts with 59 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Decreases Expression	[8]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Expression	[8]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[9]
Krueppel-like factor 4 (KLF4)	OT4O9RQW	KLF4_HUMAN	Decreases Expression	[9]
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Decreases Expression	[8]
Serine/threonine-protein kinase LATS1 (LATS1)	OTOOCG4R	LATS1_HUMAN	Decreases Expression	[8]
Aldehyde dehydrogenase 1A1 (ALDH1A1)	OTCUWZKB	AL1A1_HUMAN	Decreases Expression	[8]
Hypoxanthine-guanine phosphoribosyltransferase (HPRT1)	OTOEEEXG	HPRT_HUMAN	Decreases Expression	[8]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[8]
Pro-epidermal growth factor (EGF)	OTANRJ0L	EGF_HUMAN	Decreases Expression	[8]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Expression	[8]
Large ribosomal subunit protein uL10 (RPLP0)	OT3XKD6Y	RLA0_HUMAN	Decreases Expression	[8]
Integrin beta-1 (ITGB1)	OT6G1IAR	ITB1_HUMAN	Decreases Expression	[8]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[8]
Integrin alpha-4 (ITGA4)	OTSCAL0V	ITA4_HUMAN	Decreases Expression	[8]
Electron transfer flavoprotein subunit alpha, mitochondrial (ETFA)	OTXX61VZ	ETFA_HUMAN	Decreases Expression	[8]
Mucin-1 (MUC1)	OTHQI7IY	MUC1_HUMAN	Decreases Expression	[8]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Decreases Expression	[8]
Platelet endothelial cell adhesion molecule (PECAM1)	OTXOM4D9	PECA1_HUMAN	Decreases Expression	[8]
Epithelial cell adhesion molecule (EPCAM)	OTHBZK5X	EPCAM_HUMAN	Decreases Expression	[8]
Integrin alpha-2 (ITGA2)	OTPFL017	ITA2_HUMAN	Decreases Expression	[8]
Endoglin (ENG)	OTL2LSMI	EGLN_HUMAN	Decreases Expression	[8]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[8]
Kit ligand (KITLG)	OTB9AVQ4	SCF_HUMAN	Decreases Expression	[8]
Fibroblast growth factor receptor 2 (FGFR2)	OTLOPACK	FGFR2_HUMAN	Decreases Expression	[8]
Integrin alpha-6 (ITGA6)	OT3FA39C	ITA6_HUMAN	Decreases Expression	[8]
Signal transducer CD24 (CD24)	OT7CODJ4	CD24_HUMAN	Decreases Expression	[8]
DNA cytosine-5)-methyltransferase 1 (DNMT1)	OTM2DGTK	DNMT1_HUMAN	Decreases Expression	[8]
Hematopoietic progenitor cell antigen CD34 (CD34)	OT1MOFLZ	CD34_HUMAN	Decreases Expression	[8]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Expression	[8]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[8]
Polycomb complex protein BMI-1 (BMI1)	OTROVLJ0	BMI1_HUMAN	Decreases Expression	[8]
TGF-beta receptor type-1 (TGFBR1)	OT40S1SJ	TGFR1_HUMAN	Decreases Expression	[8]
DNA-binding protein inhibitor ID-1 (ID1)	OTKGNZN5	ID1_HUMAN	Decreases Expression	[8]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Decreases Expression	[8]
Transcription factor SOX-2 (SOX2)	OTFAWCAU	SOX2_HUMAN	Decreases Expression	[8]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Expression	[8]
Ataxin-1 (ATXN1)	OTQF0HNR	ATX1_HUMAN	Decreases Expression	[8]
Actin, cytoplasmic 1 (ACTB)	OT1MCP2F	ACTB_HUMAN	Decreases Expression	[8]
Beta-2-microglobulin (B2M)	OTDWN6NX	B2MG_HUMAN	Decreases Expression	[8]
Protein jagged-1 (JAG1)	OT3LGT6K	JAG1_HUMAN	Decreases Expression	[8]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Decreases Expression	[8]
Urokinase plasminogen activator surface receptor (PLAUR)	OTIRKKEQ	UPAR_HUMAN	Decreases Expression	[8]
Neurogenic locus notch homolog protein 2 (NOTCH2)	OTQ3Y9PA	NOTC2_HUMAN	Decreases Expression	[8]
Epithelial discoidin domain-containing receptor 1 (DDR1)	OTYW1SH8	DDR1_HUMAN	Decreases Expression	[8]
Tyrosine-protein kinase Mer (MERTK)	OTWBRAJ6	MERTK_HUMAN	Decreases Expression	[8]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Decreases Expression	[8]
Histone deacetylase 1 (HDAC1)	OTQDNOXZ	HDAC1_HUMAN	Decreases Expression	[8]
CD166 antigen (ALCAM)	OTCO4LP7	CD166_HUMAN	Decreases Expression	[8]
Flotillin-2 (FLOT2)	OTZ0QR5L	FLOT2_HUMAN	Decreases Expression	[8]
Tafazzin (TAFAZZIN)	OTDR57KI	TAZ_HUMAN	Decreases Expression	[8]
Krueppel-like factor 17 (KLF17)	OT5NWVP7	KLF17_HUMAN	Decreases Expression	[8]
Mastermind-like protein 1 (MAML1)	OTQA4DDN	MAML1_HUMAN	Decreases Expression	[8]
NAD-dependent protein deacetylase sirtuin-1 (SIRT1)	OTAYZMOY	SIR1_HUMAN	Decreases Expression	[8]
Protein smoothened (SMO)	OTXXE208	SMO_HUMAN	Decreases Expression	[8]
Forkhead box protein P1 (FOXP1)	OTSG6XGF	FOXP1_HUMAN	Decreases Expression	[8]
Homeobox protein NANOG (NANOG)	OTUEY1FM	NANOG_HUMAN	Decreases Expression	[8]
Protein lin-28 homolog A (LIN28A)	OTJJBRCQ	LN28A_HUMAN	Decreases Expression	[8]
Dachshund homolog 1 (DACH1)	OTMKNAGG	DACH1_HUMAN	Decreases Expression	[8]

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	[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	[7]
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]

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]

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]

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]

References

• [1] ClinicalTrials.gov (NCT02352558) A Study of BBI608 in Adult Patients With Advanced, Refractory Hematologic Malignancies
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] First-in-Class Cancer Stemness Inhibitor Shows Promising Results in Advanced Colorectal Cancer. 2016 ASCO GI Conference. January 26, 2016.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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] Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization
• [8] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [9] Suppression of prostate cancer progression by cancer cell stemness inhibitor napabucasin. Cancer Med. 2016 Jun;5(6):1251-8. doi: 10.1002/cam4.675. Epub 2016 Feb 21.
• [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.