Details of the Drug Combination

General Information of Drug Combination (ID: DCVESIK)

• Drug Combination Name: Flavopiridol + TAK-733
• Indication: Glioblastoma; Status: Investigative [1]
• Component Drugs:
  Flavopiridol (DMKSUOI): Small molecular drug
  TAK-733 (DMC4RNA): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: JHH-136
  Zero Interaction Potency (ZIP) Score: 68.16
  Bliss Independence Score: 74.92
  Loewe Additivity Score: 18.78
  LHighest Single Agent (HSA) Score: 21.02

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	[7]
Cyclin-dependent kinase (CDK)	TTMBO1Z	NOUNIPROTAC	Inhibitor	[8]
Myophosphorylase (PYGM)	TT31JXP	PYGM_HUMAN	Inhibitor	[8]

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	[9]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[10]

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	[11]

Flavopiridol Interacts with 42 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	[12]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[12]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[6]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[13]
Serine protease HTRA2, mitochondrial (HTRA2)	OTC7616F	HTRA2_HUMAN	Affects Localization	[6]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[15]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Activity	[16]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Activity	[6]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[17]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[18]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Expression	[19]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Activity	[6]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Decreases Activity	[16]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[6]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Affects Expression	[20]
High mobility group protein HMG-I/HMG-Y (HMGA1)	OTQUSHPX	HMGA1_HUMAN	Decreases Expression	[5]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Activity	[16]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Expression	[21]
DNA-directed RNA polymerase II subunit RPB1 (POLR2A)	OTHJQ1DZ	RPB1_HUMAN	Decreases Expression	[5]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Activity	[6]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[22]
Retinoblastoma-like protein 1 (RBL1)	OTDEBFYC	RBL1_HUMAN	Decreases Expression	[23]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[21]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Decreases Expression	[5]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[24]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Cleavage	[25]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Expression	[12]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[17]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Cleavage	[26]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[17]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Decreases Expression	[27]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Decreases Expression	[5]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[27]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[6]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[6]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[6]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[28]
BAG family molecular chaperone regulator 1 (BAG1)	OTRQNIA4	BAG1_HUMAN	Decreases Expression	[18]
Diablo IAP-binding mitochondrial protein (DIABLO)	OTHJ9MCZ	DBLOH_HUMAN	Affects Localization	[6]
Glycogen phosphorylase, brain form (PYGB)	OT2ZTJT0	PYGB_HUMAN	Affects Binding	[29]
Glycogen phosphorylase, liver form (PYGL)	OTS1YFGR	PYGL_HUMAN	Affects Binding	[29]

Indication(s) of TAK-733

Disease Entry	ICD 11	Status	REF
Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]

TAK-733 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MAPK/ERK kinase kinase (MAP3K)	TTROQ37	NOUNIPROTAC	Modulator	[30]

References

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• [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] ClinicalTrials.gov (NCT00948467) Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies. U.S. National Institutes of Health.
• [5] 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.
• [6] 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.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Pharma & Vaccines. Product Development Pipeline. April 29 2009.
• [9] 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.
• [10] Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011 Mar;63(1):157-81.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood. 1998 Nov 15;92(10):3804-16.
• [16] 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.
• [17] 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.
• [18] 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.
• [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] 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.
• [22] Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood. 2004 Jul 15;104(2):509-18. doi: 10.1182/blood-2003-12-4121. Epub 2004 Mar 23.
• [23] Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. Clin Cancer Res. 1998 Nov;4(11):2885-90.
• [24] Flavopiridol induces apoptosis and caspase-3 activation of a newly characterized Burkitt's lymphoma cell line containing mutant p53 genes. Blood Cells Mol Dis. 2001 May-Jun;27(3):610-24. doi: 10.1006/bcmd.2001.0428.
• [25] 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.
• [26] 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.
• [27] Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway. Mol Cancer Ther. 2003 Feb;2(2):139-50.
• [28] Bcl-2 independence of flavopiridol-induced apoptosis. Mitochondrial depolarization in the absence of cytochrome c release. J Biol Chem. 2000 Oct 13;275(41):32089-97. doi: 10.1074/jbc.M005267200.
• [29] 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.
• [30] MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013; 6: 27.