Details of the Drug Combination

General Information of Drug Combination (ID: DCPJKXG)

• Drug Combination Name: Flavopiridol + Fludarabine
• Indication: B-cell Chronic Lymphocytic Leukemia; Status: Phase 1 [1]
• Component Drugs:
  Flavopiridol (DMKSUOI): Small molecular drug
  Fludarabine (DMVRLT7): Small molecular drug

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	[8]
Cyclin-dependent kinase (CDK)	TTMBO1Z	NOUNIPROTAC	Inhibitor	[9]
Myophosphorylase (PYGM)	TT31JXP	PYGM_HUMAN	Inhibitor	[9]

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	[10]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[11]

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	[12]

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	[13]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[7]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[14]
Serine protease HTRA2, mitochondrial (HTRA2)	OTC7616F	HTRA2_HUMAN	Affects Localization	[7]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[15]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Activity	[16]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[17]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Expression	[18]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Affects Expression	[19]
DNA-directed RNA polymerase II subunit RPB1 (POLR2A)	OTHJQ1DZ	RPB1_HUMAN	Decreases Expression	[6]
Retinoblastoma-like protein 1 (RBL1)	OTDEBFYC	RBL1_HUMAN	Decreases Expression	[20]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[21]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Cleavage	[22]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Expression	[13]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Cleavage	[23]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[17]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Decreases Expression	[6]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[7]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[7]
BAG family molecular chaperone regulator 1 (BAG1)	OTRQNIA4	BAG1_HUMAN	Decreases Expression	[24]
Diablo IAP-binding mitochondrial protein (DIABLO)	OTHJ9MCZ	DBLOH_HUMAN	Affects Localization	[7]
Glycogen phosphorylase, brain form (PYGB)	OT2ZTJT0	PYGB_HUMAN	Affects Binding	[25]
Glycogen phosphorylase, liver form (PYGL)	OTS1YFGR	PYGL_HUMAN	Affects Binding	[25]

Indication(s) of Fludarabine

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[4]
Cutaneous melanoma	2C30	Approved	[4]
Haematological malignancy	2B33.Y	Approved	[5]
Hematologic disease	3C0Z	Approved	[4]
Hepatosplenic T-cell lymphoma	N.A.	Approved	[4]
Immunodeficiency	4A00-4A85	Approved	[4]
Large granular lymphocytic leukemia	2A90.1	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
MALT lymphoma	N.A.	Approved	[4]
Multiple sclerosis	8A40	Approved	[4]
Myeloproliferative neoplasm	2A20	Approved	[4]
Nodal marginal zone lymphoma	2A85.0	Approved	[4]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[4]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[4]
Small intestine lymphoma	N.A.	Approved	[4]
Splenic marginal zone lymphoma	N.A.	Approved	[4]
Systemic lupus erythematosus	4A40.0	Approved	[4]
Systemic sclerosis	4A42	Approved	[4]
Testicular lymphoma	N.A.	Approved	[4]
Classic Hodgkin lymphoma	N.A.	Investigative	[4]
Colon cancer	2B90.Z	Investigative	[4]
Gastric cancer	2B72	Investigative	[4]
Neuroblastoma	2D11.2	Investigative	[4]

Fludarabine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine deaminase (ADA)	TTLP57V	ADA_HUMAN	Inhibitor	[29]

Fludarabine Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Affects Expression	[30]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[31]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[26]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[32]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[27]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[27]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[33]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[34]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[35]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[28]

References

• [1] ClinicalTrials.gov (NCT00058227) Alvocidib, Fludarabine Phosphate, and Rituximab in Treating Patients With Lymphoproliferative Disorders or Mantle Cell Lymphoma
• [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] Fludarabine FDA Label
• [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: 4802).
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• [7] 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.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Pharma & Vaccines. Product Development Pipeline. April 29 2009.
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• [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.
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• [25] 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.
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• [28] MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood. 2006 May 15;107(10):4109-14. doi: 10.1182/blood-2005-08-3273. Epub 2006 Jan 26.
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• [33] Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2006 May 15;107(10):4122-9. doi: 10.1182/blood-2005-11-4465. Epub 2006 Jan 26.
• [34] Comparative effects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells. Br J Nutr. 2012 Mar;107(6):781-90. doi: 10.1017/S0007114511003631. Epub 2011 Aug 1.
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