Details of the Drug Combination

General Information of Drug Combination (ID: DCEC7I3)

• Drug Combination Name: Flavopiridol + Ibrutinib
• Indication: Diffuse large B cell lymphoma; Status: Investigative [1]
• Component Drugs:
  Flavopiridol (DMKSUOI): Small molecular drug
  Ibrutinib (DMHZCPO): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TMD8
  Zero Interaction Potency (ZIP) Score: 9.85
  Bliss Independence Score: 8.17
  Loewe Additivity Score: 5.85
  LHighest Single Agent (HSA) Score: 7.99

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Flavopiridol

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Phase 2	[2]
Chronic lymphocytic leukaemia	2A82.0	Discontinued in Phase 3	[3]

Flavopiridol Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 9 (CDK9)	TT1LVF2	CDK9_HUMAN	Inhibitor	[6]
Cyclin-dependent kinase (CDK)	TTMBO1Z	NOUNIPROTAC	Inhibitor	[10]
Myophosphorylase (PYGM)	TT31JXP	PYGM_HUMAN	Inhibitor	[10]

Flavopiridol Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[12]

Flavopiridol Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[13]

Flavopiridol Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Increases Expression	[14]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[14]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[9]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[15]
Serine protease HTRA2, mitochondrial (HTRA2)	OTC7616F	HTRA2_HUMAN	Affects Localization	[9]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[16]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Activity	[17]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[18]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Expression	[19]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Affects Expression	[20]
DNA-directed RNA polymerase II subunit RPB1 (POLR2A)	OTHJQ1DZ	RPB1_HUMAN	Decreases Expression	[8]
Retinoblastoma-like protein 1 (RBL1)	OTDEBFYC	RBL1_HUMAN	Decreases Expression	[21]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[22]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Cleavage	[23]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Expression	[14]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Cleavage	[24]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[18]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Decreases Expression	[8]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[9]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[9]
BAG family molecular chaperone regulator 1 (BAG1)	OTRQNIA4	BAG1_HUMAN	Decreases Expression	[25]
Diablo IAP-binding mitochondrial protein (DIABLO)	OTHJ9MCZ	DBLOH_HUMAN	Affects Localization	[9]
Glycogen phosphorylase, brain form (PYGB)	OT2ZTJT0	PYGB_HUMAN	Affects Binding	[26]
Glycogen phosphorylase, liver form (PYGL)	OTS1YFGR	PYGL_HUMAN	Affects Binding	[26]

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	[6]
Diffuse large B-cell lymphoma	2A81	Phase 3	[6]
Follicular lymphoma	2A80	Phase 3	[6]
Non-hodgkin lymphoma	2B33.5	Phase 3	[6]
Pancreatic cancer	2C10	Phase 3	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[7]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]

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	[27]

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	[28]

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	[29]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[29]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[29]

Ibrutinib Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[30]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Decreases Expression	[30]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)	OTGVC9MY	PLCG2_HUMAN	Decreases Phosphorylation	[30]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Decreases Expression	[30]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Affects Localization	[30]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[30]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[30]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[31]
TNF receptor-associated factor 2 (TRAF2)	OT1MEZZN	TRAF2_HUMAN	Decreases Response To Substance	[30]
TNF receptor-associated factor 3 (TRAF3)	OT5TQBGV	TRAF3_HUMAN	Decreases Response To Substance	[30]
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14)	OTT3DOOL	M3K14_HUMAN	Decreases Response To Substance	[30]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [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: 5680).
• [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] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization
• [8] Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood. 2011 Mar 24;117(12):3302-10. doi: 10.1182/blood-2010-09-310862. Epub 2011 Jan 14.
• [9] Flavopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis. Cancer Res. 2003 Jan 1;63(1):93-9.
• [10] Pharma & Vaccines. Product Development Pipeline. April 29 2009.
• [11] The novel BCR-ABL and FLT3 inhibitor ponatinib is a potent inhibitor of the MDR-associated ATP-binding cassette transporter ABCG2. Mol Cancer Ther. 2012 Sep;11(9):2033-44.
• [12] Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011 Mar;63(1):157-81.
• [13] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [14] The cyclin-dependent kinase inhibitor flavopiridol sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis. Int J Mol Med. 2006 Aug;18(2):249-56.
• [15] Flavopiridol induces cellular FLICE-inhibitory protein degradation by the proteasome and promotes TRAIL-induced early signaling and apoptosis in breast tumor cells. Cancer Res. 2006 Sep 1;66(17):8858-69. doi: 10.1158/0008-5472.CAN-06-0808.
• [16] Identification and Profiling of Environmental Chemicals That Inhibit the TGF/SMAD Signaling Pathway. Chem Res Toxicol. 2019 Dec 16;32(12):2433-2444. doi: 10.1021/acs.chemrestox.9b00228. Epub 2019 Nov 11.
• [17] Flavopiridol inhibits smooth muscle cell proliferation in vitro and neointimal formation In vivo after carotid injury in the rat. Circulation. 1999 Aug 10;100(6):659-65. doi: 10.1161/01.cir.100.6.659.
• [18] Loss of the Bcl-2 phosphorylation loop domain is required to protect human myeloid leukemia cells from flavopiridol-mediated mitochondrial damage and apoptosis. Cancer Biol Ther. 2002 Mar-Apr;1(2):136-44. doi: 10.4161/cbt.58.
• [19] Flavopiridol targets c-KIT transcription and induces apoptosis in gastrointestinal stromal tumor cells. Cancer Res. 2006 Jun 1;66(11):5858-66. doi: 10.1158/0008-5472.CAN-05-2933.
• [20] Flavopiridol enhances human tumor cell radiosensitivity and prolongs expression of gammaH2AX foci. Mol Cancer Ther. 2004 Apr;3(4):409-16.
• [21] Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. Clin Cancer Res. 1998 Nov;4(11):2885-90.
• [22] Abrogation of p21 expression by flavopiridol enhances depsipeptide-mediated apoptosis in malignant pleural mesothelioma cells. Clin Cancer Res. 2004 Mar 1;10(5):1813-25. doi: 10.1158/1078-0432.ccr-0901-3.
• [23] Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. Clin Cancer Res. 1999 Oct;5(10):2925-38.
• [24] The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in human leukemia cells (U937) through the mitochondrial rather than the receptor-mediated pathway. Cell Death Differ. 2001 Jul;8(7):715-24. doi: 10.1038/sj.cdd.4400868.
• [25] Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005 Oct 1;106(7):2513-9. doi: 10.1182/blood-2005-04-1678. Epub 2005 Jun 21.
• [26] The cyclin-dependent kinase (CDK) inhibitor flavopiridol inhibits glycogen phosphorylase. Arch Biochem Biophys. 2001 Feb 15;386(2):179-87. doi: 10.1006/abbi.2000.2220.
• [27] 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).
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.