Details of the Drug Combination

General Information of Drug Combination (ID: DCMW9C0)

Drug Combination Name

PD-0325901 Fludarabine

Indication

Disease Entry	Status	REF
Ewing sarcoma	Investigative	[1]

Component Drugs

PD-0325901 DM27D4J

Fludarabine DMVRLT7

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: TC-71

Zero Interaction Potency (ZIP) Score: 9.81

Bliss Independence Score: 10.41

Loewe Additivity Score: 0.01

LHighest Single Agent (HSA) Score: 3.57

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of PD-0325901

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 2	[2]

PD-0325901 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MAPK/ERK kinase kinase (MAP3K)	TTROQ37	NOUNIPROTAC	Modulator	[6]
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PD-0325901 Interacts with 84 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[7]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Expression	[7]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Increases Expression	[7]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Decreases Expression	[7]
Toll-like receptor 4 (TLR4)	OTP7ML3S	TLR4_HUMAN	Decreases Expression	[5]
Neuropilin-1 (NRP1)	OTCGULYV	NRP1_HUMAN	Decreases Expression	[5]
T-box transcription factor TBX3 (TBX3)	OTM64N7K	TBX3_HUMAN	Decreases Expression	[5]
Protein sprouty homolog 2 (SPRY2)	OTH0CRCZ	SPY2_HUMAN	Decreases Expression	[5]
Leupaxin (LPXN)	OTUNV3CK	LPXN_HUMAN	Decreases Expression	[5]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Decreases Expression	[5]
Slit homolog 2 protein (SLIT2)	OTLS2RJ4	SLIT2_HUMAN	Decreases Expression	[5]
Tumor necrosis factor ligand superfamily member 15 (TNFSF15)	OTNGA2BW	TNF15_HUMAN	Decreases Expression	[5]
Integrin beta-like protein 1 (ITGBL1)	OTJDHE17	ITGBL_HUMAN	Decreases Expression	[5]
Urokinase-type plasminogen activator (PLAU)	OTX0QGKK	UROK_HUMAN	Decreases Expression	[5]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[5]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Expression	[5]
Glycophorin-C (GYPC)	OTOEDR7O	GLPC_HUMAN	Decreases Expression	[5]
Growth-regulated alpha protein (CXCL1)	OT3WCTZV	GROA_HUMAN	Decreases Expression	[5]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[5]
Tissue factor pathway inhibitor (TFPI)	OTA0FX16	TFPI1_HUMAN	Decreases Expression	[5]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Expression	[5]
Aminopeptidase N (ANPEP)	OTP3WYFD	AMPN_HUMAN	Decreases Expression	[5]
Integrin alpha-2 (ITGA2)	OTPFL017	ITA2_HUMAN	Decreases Expression	[5]
Protein-glutamine gamma-glutamyltransferase 2 (TGM2)	OT6MFOWF	TGM2_HUMAN	Decreases Expression	[5]
Pentraxin-related protein PTX3 (PTX3)	OTPXHRKU	PTX3_HUMAN	Decreases Expression	[5]
5-hydroxytryptamine receptor 7 (HTR7)	OT44DEWB	5HT7R_HUMAN	Decreases Expression	[5]
Glutaredoxin-1 (GLRX)	OT0QHTAR	GLRX1_HUMAN	Decreases Expression	[5]
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2)	OT3K7HY5	DHB2_HUMAN	Decreases Expression	[5]
ETS translocation variant 5 (ETV5)	OTE2OBM4	ETV5_HUMAN	Decreases Expression	[5]
ETS translocation variant 4 (ETV4)	OT8C98UZ	ETV4_HUMAN	Decreases Expression	[5]
Transcription factor SOX-9 (SOX9)	OTVDJFGN	SOX9_HUMAN	Decreases Expression	[5]
ETS translocation variant 1 (ETV1)	OT6PMJIK	ETV1_HUMAN	Decreases Expression	[5]
Stanniocalcin-1 (STC1)	OTGVVXYF	STC1_HUMAN	Decreases Expression	[5]
Paired mesoderm homeobox protein 1 (PRRX1)	OTTZK5G8	PRRX1_HUMAN	Decreases Expression	[5]
Epithelial membrane protein 1 (EMP1)	OTSZHUHQ	EMP1_HUMAN	Decreases Expression	[5]
Forkhead box protein G1 (FOXG1)	OTAW57J4	FOXG1_HUMAN	Decreases Expression	[5]
ADP-ribosylation factor-like protein 4C (ARL4C)	OTQ3QNNU	ARL4C_HUMAN	Decreases Expression	[5]
Reelin (RELN)	OTLKMW1O	RELN_HUMAN	Decreases Expression	[5]
C-C motif chemokine 20 (CCL20)	OTUCJY4N	CCL20_HUMAN	Decreases Expression	[5]
A-kinase anchor protein 12 (AKAP12)	OTCVRDDX	AKA12_HUMAN	Decreases Expression	[5]
Urokinase plasminogen activator surface receptor (PLAUR)	OTIRKKEQ	UPAR_HUMAN	Decreases Expression	[5]
Dual specificity protein phosphatase 4 (DUSP4)	OT6WAO12	DUS4_HUMAN	Decreases Expression	[5]
Semaphorin-3A (SEMA3A)	OTQJSV7W	SEM3A_HUMAN	Decreases Expression	[5]
Monocyte to macrophage differentiation factor (MMD)	OTB5I4OC	PAQRB_HUMAN	Decreases Expression	[5]
Syntaxin-1A (STX1A)	OTSBUZB4	STX1A_HUMAN	Decreases Expression	[5]
Dual specificity protein phosphatase 6 (DUSP6)	OT4H6RKW	DUS6_HUMAN	Decreases Expression	[5]
Kinesin-like protein KIF24 (KIF24)	OTJTA5V3	KIF24_HUMAN	Decreases Expression	[5]
Anoctamin-1 (ANO1)	OTSREUNI	ANO1_HUMAN	Decreases Expression	[5]
NADH-cytochrome b5 reductase 2 (CYB5R2)	OTTLM7XN	NB5R2_HUMAN	Decreases Expression	[5]
Dynamin-binding protein (DNMBP)	OTMHH14H	DNMBP_HUMAN	Decreases Expression	[5]
Sialic acid-binding Ig-like lectin 15 (SIGLEC15)	OTON4K9S	SIG15_HUMAN	Decreases Expression	[5]
UPF0606 protein KIAA1549L (KIAA1549L)	OT80HUVY	K154L_HUMAN	Decreases Expression	[5]
Neuron navigator 3 (NAV3)	OT97M1TR	NAV3_HUMAN	Decreases Expression	[5]
Dedicator of cytokinesis protein 4 (DOCK4)	OTH3XY8B	DOCK4_HUMAN	Decreases Expression	[5]
Transmembrane protein 156 (TMEM156)	OTH7YJID	TM156_HUMAN	Decreases Expression	[5]
Tribbles homolog 2 (TRIB2)	OTHSX3MX	TRIB2_HUMAN	Decreases Expression	[5]
Hyaluronan synthase 2 (HAS2)	OTTD3PAL	HYAS2_HUMAN	Decreases Expression	[5]
Neuronal cell adhesion molecule (NRCAM)	OT80HHQ2	NRCAM_HUMAN	Decreases Expression	[5]
Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2)	OTB71I02	DCBD2_HUMAN	Decreases Expression	[5]
Formin-like protein 2 (FMNL2)	OT9OVWCV	FMNL2_HUMAN	Decreases Expression	[5]
Monoglyceride lipase (MGLL)	OT5ES4IE	MGLL_HUMAN	Decreases Expression	[5]
Paternally-expressed gene 3 protein (PEG3)	OTHQW98S	PEG3_HUMAN	Decreases Expression	[5]
Disintegrin and metalloproteinase domain-containing protein 19 (ADAM19)	OTH88TXU	ADA19_HUMAN	Decreases Expression	[5]
Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15)	OTGMPVNR	S6A15_HUMAN	Decreases Expression	[5]
Endothelial cell-specific molecule 1 (ESM1)	OT331Y8V	ESM1_HUMAN	Decreases Expression	[5]
Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1)	OTW3T4B2	IRPL1_HUMAN	Decreases Expression	[5]
Neurotrimin (NTM)	OTHF0UQU	NTRI_HUMAN	Decreases Expression	[5]
Histone deacetylase 9 (HDAC9)	OTO8O0LF	HDAC9_HUMAN	Decreases Expression	[5]
Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6)	OTB17Q43	SIA10_HUMAN	Decreases Expression	[5]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[8]
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Increases Expression	[9]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[10]
DNA excision repair protein ERCC-1 (ERCC1)	OTNPYQHI	ERCC1_HUMAN	Decreases Expression	[11]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[12]
Fos-related antigen 1 (FOSL1)	OT9YTYMB	FOSL1_HUMAN	Decreases Expression	[13]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[14]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[14]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[12]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[15]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Decreases Activity	[16]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[8]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[12]
DNA repair endonuclease XPF (ERCC4)	OTFIOPG1	XPF_HUMAN	Increases Expression	[11]
Ras-related C3 botulinum toxin substrate 1 (RAC1)	OTKRO61U	RAC1_HUMAN	Affects Response To Substance	[17]
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⏷ Show the Full List of 84 DOT(s)

Indication(s) of Fludarabine

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

Fludarabine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine deaminase (ADA)	TTLP57V	ADA_HUMAN	Inhibitor	[21]
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Fludarabine Interacts with 22 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	[22]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[23]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[23]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Increases Expression	[24]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Increases Expression	[25]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[18]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[26]
DNA cytosine-5)-methyltransferase 1 (DNMT1)	OTM2DGTK	DNMT1_HUMAN	Decreases Expression	[27]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[19]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[19]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Activity	[28]
Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2)	OTUE7Z91	MP2K2_HUMAN	Increases Activity	[28]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[24]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[26]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[27]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)	OT4Y9NQI	MP2K1_HUMAN	Increases Activity	[28]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[25]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[25]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[26]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[19]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[20]
Growth/differentiation factor 15 (GDF15)	OTWQN50N	GDF15_HUMAN	Increases Expression	[24]
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⏷ Show the Full List of 22 DOT(s)

References

1	Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
2	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: 7935).
3	Fludarabine FDA Label
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: 4802).
5	PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
6	MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013; 6: 27.
7	U0126, a mitogen-activated protein kinase kinase 1 and 2 (MEK1 and 2) inhibitor, selectively up-regulates main isoforms of CYP3A subfamily via a pregnane X receptor (PXR) in HepG2 cells. Arch Toxicol. 2014 Dec;88(12):2243-59.
8	Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer. Cancer Lett. 2014 Jun 1;347(2):204-11. doi: 10.1016/j.canlet.2014.02.018. Epub 2014 Feb 24.
9	Antitumor activity of luteolin in human colon cancer SW620 cells is mediated by the ERK/FOXO3a signaling pathway. Toxicol In Vitro. 2020 Aug;66:104852. doi: 10.1016/j.tiv.2020.104852. Epub 2020 Apr 5.
10	Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
11	Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance. Oncogene. 2012 May 10;31(19):2412-22. doi: 10.1038/onc.2011.426. Epub 2011 Sep 26.
12	Blocking downstream signaling pathways in the context of HDAC inhibition promotes apoptosis preferentially in cells harboring mutant Ras. Oncotarget. 2016 Oct 25;7(43):69804-69815. doi: 10.18632/oncotarget.12001.
13	MEK inhibitor PD-0325901 overcomes resistance to CK2 inhibitor CX-4945 and exhibits anti-tumor activity in head and neck cancer. Int J Biol Sci. 2015 Feb 23;11(4):411-22. doi: 10.7150/ijbs.10745. eCollection 2015.
14	The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition. Br J Cancer. 2012 Apr 10;106(8):1386-94. doi: 10.1038/bjc.2012.70. Epub 2012 Mar 13.
15	Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors. Eur J Cancer. 2013 Dec;49(18):3936-44. doi: 10.1016/j.ejca.2013.08.007. Epub 2013 Sep 3.
16	A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
17	Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. Genome Res. 2012 Dec;22(12):2315-27. doi: 10.1101/gr.140988.112. Epub 2012 Oct 2.
18	Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824/fludarabine antileukemic interactions. Mol Cancer Ther. 2008 Oct;7(10):3285-97. doi: 10.1158/1535-7163.MCT-08-0385.
19	9-beta-D-arabinofuranosyl-2-fluoroadenine inhibits expression of vascular endothelial growth factor through hypoxia-inducible factor-1 in human ovarian cancer cells. Mol Pharmacol. 2004 Jul;66(1):178-86. doi: 10.1124/mol.66.1.178.
20	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.
21	Purine nucleoside analogs in indolent non-Hodgkin's lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5.
22	Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene. 2003 Nov 13;22(51):8356-69. doi: 10.1038/sj.onc.1207004.
23	Differential effects of chemotherapeutic drugs versus the MDM-2 antagonist nutlin-3 on cell cycle progression and induction of apoptosis in SKW6.4 lymphoblastoid B-cells. J Cell Biochem. 2008 May 15;104(2):595-605. doi: 10.1002/jcb.21649.
24	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.
25	Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide. PLoS One. 2014 Jun 23;9(6):e99993. doi: 10.1371/journal.pone.0099993. eCollection 2014.
26	Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation. Blood. 2001 Nov 1;98(9):2800-7. doi: 10.1182/blood.v98.9.2800.
27	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.
28	The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells. Cancer Res. 2004 Apr 1;64(7):2590-600. doi: 10.1158/0008-5472.can-03-2631.