Details of the Drug Combination

General Information of Drug Combination (ID: DCXCTN2)

• Drug Combination Name: AT7519 + PF-3758309
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  AT7519 (DMCE08M): Small molecular drug
  PF-3758309 (DM36PKZ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 10.764
  Bliss Independence Score: 11.477
  Loewe Additivity Score: 12.19
  LHighest Single Agent (HSA) Score: 15.416

Molecular Interaction Atlas of This Drug Combination

Indication(s) of AT7519

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

AT7519 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[4]

AT7519 Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Increases Expression	[5]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Decreases Expression	[5]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[5]
M-phase inducer phosphatase 1 (CDC25A)	OTSLKKCO	MPIP1_HUMAN	Decreases Expression	[5]
M-phase inducer phosphatase 2 (CDC25B)	OT12MSRY	MPIP2_HUMAN	Decreases Expression	[5]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[5]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[5]
Forkhead box protein O4 (FOXO4)	OT90X9LN	FOXO4_HUMAN	Increases Expression	[5]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[5]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[5]
Ubiquitin-like-conjugating enzyme ATG10 (ATG10)	OTVRPC5X	ATG10_HUMAN	Decreases Expression	[5]

Indication(s) of PF-3758309

Disease Entry	ICD 11	Status	REF
Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]

PF-3758309 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
PAK-4 protein kinase (PAK4)	TT7Y3BZ	PAK4_HUMAN	Inhibitor	[3]

PF-3758309 Interacts with 48 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase PAK 4 (PAK4)	OTY8JEE4	PAK4_HUMAN	Increases Response To Substance	[6]
Suppressor of cytokine signaling 3 (SOCS3)	OTY183WJ	SOCS3_HUMAN	Decreases Expression	[6]
T-box transcription factor TBX3 (TBX3)	OTM64N7K	TBX3_HUMAN	Increases Expression	[6]
Receptor-interacting serine/threonine-protein kinase 2 (RIPK2)	OT0KMIYQ	RIPK2_HUMAN	Decreases Expression	[6]
Tumor necrosis factor ligand superfamily member 14 (TNFSF14)	OT5QRF09	TNF14_HUMAN	Increases Expression	[6]
Nucleolar protein 3 (NOL3)	OT1K0L0D	NOL3_HUMAN	Increases Expression	[6]
STAM-binding protein (STAMBP)	OTOT2OXM	STABP_HUMAN	Decreases Expression	[6]
Interferon alpha-2 (IFNA2)	OT4GII73	IFNA2_HUMAN	Increases Expression	[6]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[6]
Alpha-crystallin B chain (CRYAB)	OTY4JGYU	CRYAB_HUMAN	Increases Expression	[6]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[6]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[6]
CCAAT/enhancer-binding protein beta (CEBPB)	OTM9MQIA	CEBPB_HUMAN	Decreases Expression	[6]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[6]
Azurocidin (AZU1)	OTHXU264	CAP7_HUMAN	Decreases Expression	[6]
Brain-derived neurotrophic factor (BDNF)	OTLGH7EW	BDNF_HUMAN	Increases Expression	[6]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[6]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[6]
Caspase-1 (CASP1)	OTZ3YQFU	CASP1_HUMAN	Decreases Expression	[6]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Increases Expression	[6]
Tumor necrosis factor ligand superfamily member 8 (TNFSF8)	OTDYGDJ3	TNFL8_HUMAN	Decreases Expression	[6]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[6]
B-cell lymphoma 6 protein (BCL6)	OTQAWWO1	BCL6_HUMAN	Increases Expression	[6]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Decreases Expression	[6]
Protein kinase C zeta type (PRKCZ)	OTN2FE42	KPCZ_HUMAN	Increases Expression	[6]
Elongation factor 1-alpha 2 (EEF1A2)	OT9Z23K5	EF1A2_HUMAN	Increases Expression	[6]
Lymphotoxin-beta (LTB)	OTUFS8CF	TNFC_HUMAN	Increases Expression	[6]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Decreases Expression	[6]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[6]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[6]
C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2)	OTDUHLN0	JIP2_HUMAN	Increases Expression	[6]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[6]
Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD)	OTBOSJHO	TRADD_HUMAN	Increases Expression	[6]
Bcl-2-related protein A1 (BCL2A1)	OTWRYSNA	B2LA1_HUMAN	Decreases Expression	[6]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[6]
Gamma-interferon-inducible protein 16 (IFI16)	OT4SPU0U	IF16_HUMAN	Decreases Expression	[6]
Quinone oxidoreductase PIG3 (TP53I3)	OTSCM68G	QORX_HUMAN	Increases Expression	[6]
Ectodysplasin-A (EDA)	OTAKS5WS	EDA_HUMAN	Increases Expression	[6]
Bcl-2-like protein 2 (BCL2L2)	OTMKVO0J	B2CL2_HUMAN	Increases Expression	[6]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[6]
Homeobox protein Nkx-3.1 (NKX3-1)	OT0DO6ZU	NKX31_HUMAN	Increases Expression	[6]
Caspase recruitment domain-containing protein 6 (CARD6)	OTEI1PJ1	CARD6_HUMAN	Decreases Expression	[6]
Protein AATF (AATF)	OT1QOKLD	AATF_HUMAN	Decreases Expression	[6]
Bcl-2-associated transcription factor 1 (BCLAF1)	OT7T8H6A	BCLF1_HUMAN	Decreases Expression	[6]
Serine/threonine-protein kinase pim-2 (PIM2)	OTHQGU3I	PIM2_HUMAN	Decreases Expression	[6]
Tumor necrosis factor receptor superfamily member 10D (TNFRSF10D)	OTOSRDJT	TR10D_HUMAN	Decreases Expression	[6]
Tumor necrosis factor ligand superfamily member 18 (TNFSF18)	OT3ANRX1	TNF18_HUMAN	Decreases Expression	[6]
TNF receptor-associated factor 6 (TRAF6)	OTA5GO5K	TRAF6_HUMAN	Increases Expression	[6]

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] ClinicalTrials.gov (NCT02503709) Onalespib and CDKI AT7519 in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery in National Cancer Institute (NCI).
• [3] Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9446-51.
• [4] Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther. 2009 Feb;8(2):324-32.
• [5] CDK Blockade Using AT7519 Suppresses Acute Myeloid Leukemia Cell Survival through the Inhibition of Autophagy and Intensifies the Anti-leukemic Effect of Arsenic Trioxide. Iran J Pharm Res. 2019 Fall;18(Suppl1):119-131. doi: 10.22037/ijpr.2019.112560.13827.
• [6] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.