Details of the Drug Combination

General Information of Drug Combination (ID: DCG3M3L)

Drug Combination Name

SCH 727965 PF-3758309

Indication

Disease Entry	Status	REF
Ewing sarcoma	Investigative	[1]

Component Drugs

SCH 727965 DMCJLD1

PF-3758309 DM36PKZ

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: TC-71

Zero Interaction Potency (ZIP) Score: 12.519

Bliss Independence Score: 12.052

Loewe Additivity Score: 9.734

LHighest Single Agent (HSA) Score: 12.654

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of SCH 727965

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Discontinued in Phase 3	[2]

SCH 727965 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	[4]
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[4]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[4]
------------------------------------------------------------------------------------

SCH 727965 Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[5]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[5]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Decreases Expression	[6]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[6]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[6]
Fanconi anemia group D2 protein (FANCD2)	OTVEB5LF	FACD2_HUMAN	Decreases Expression	[6]
Cyclin-dependent kinase 12 (CDK12)	OTZUDGNU	CDK12_HUMAN	Decreases Activity	[6]
------------------------------------------------------------------------------------


⏷ Show the Full List of 7 DOT(s)

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	[7]
Suppressor of cytokine signaling 3 (SOCS3)	OTY183WJ	SOCS3_HUMAN	Decreases Expression	[7]
T-box transcription factor TBX3 (TBX3)	OTM64N7K	TBX3_HUMAN	Increases Expression	[7]
Receptor-interacting serine/threonine-protein kinase 2 (RIPK2)	OT0KMIYQ	RIPK2_HUMAN	Decreases Expression	[7]
Tumor necrosis factor ligand superfamily member 14 (TNFSF14)	OT5QRF09	TNF14_HUMAN	Increases Expression	[7]
Nucleolar protein 3 (NOL3)	OT1K0L0D	NOL3_HUMAN	Increases Expression	[7]
STAM-binding protein (STAMBP)	OTOT2OXM	STABP_HUMAN	Decreases Expression	[7]
Interferon alpha-2 (IFNA2)	OT4GII73	IFNA2_HUMAN	Increases Expression	[7]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[7]
Alpha-crystallin B chain (CRYAB)	OTY4JGYU	CRYAB_HUMAN	Increases Expression	[7]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[7]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[7]
CCAAT/enhancer-binding protein beta (CEBPB)	OTM9MQIA	CEBPB_HUMAN	Decreases Expression	[7]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[7]
Azurocidin (AZU1)	OTHXU264	CAP7_HUMAN	Decreases Expression	[7]
Brain-derived neurotrophic factor (BDNF)	OTLGH7EW	BDNF_HUMAN	Increases Expression	[7]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[7]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[7]
Caspase-1 (CASP1)	OTZ3YQFU	CASP1_HUMAN	Decreases Expression	[7]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Increases Expression	[7]
Tumor necrosis factor ligand superfamily member 8 (TNFSF8)	OTDYGDJ3	TNFL8_HUMAN	Decreases Expression	[7]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[7]
B-cell lymphoma 6 protein (BCL6)	OTQAWWO1	BCL6_HUMAN	Increases Expression	[7]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Decreases Expression	[7]
Protein kinase C zeta type (PRKCZ)	OTN2FE42	KPCZ_HUMAN	Increases Expression	[7]
Elongation factor 1-alpha 2 (EEF1A2)	OT9Z23K5	EF1A2_HUMAN	Increases Expression	[7]
Lymphotoxin-beta (LTB)	OTUFS8CF	TNFC_HUMAN	Increases Expression	[7]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Decreases Expression	[7]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[7]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[7]
C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2)	OTDUHLN0	JIP2_HUMAN	Increases Expression	[7]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[7]
Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD)	OTBOSJHO	TRADD_HUMAN	Increases Expression	[7]
Bcl-2-related protein A1 (BCL2A1)	OTWRYSNA	B2LA1_HUMAN	Decreases Expression	[7]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[7]
Gamma-interferon-inducible protein 16 (IFI16)	OT4SPU0U	IF16_HUMAN	Decreases Expression	[7]
Quinone oxidoreductase PIG3 (TP53I3)	OTSCM68G	QORX_HUMAN	Increases Expression	[7]
Ectodysplasin-A (EDA)	OTAKS5WS	EDA_HUMAN	Increases Expression	[7]
Bcl-2-like protein 2 (BCL2L2)	OTMKVO0J	B2CL2_HUMAN	Increases Expression	[7]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[7]
Homeobox protein Nkx-3.1 (NKX3-1)	OT0DO6ZU	NKX31_HUMAN	Increases Expression	[7]
Caspase recruitment domain-containing protein 6 (CARD6)	OTEI1PJ1	CARD6_HUMAN	Decreases Expression	[7]
Protein AATF (AATF)	OT1QOKLD	AATF_HUMAN	Decreases Expression	[7]
Bcl-2-associated transcription factor 1 (BCLAF1)	OT7T8H6A	BCLF1_HUMAN	Decreases Expression	[7]
Serine/threonine-protein kinase pim-2 (PIM2)	OTHQGU3I	PIM2_HUMAN	Decreases Expression	[7]
Tumor necrosis factor receptor superfamily member 10D (TNFRSF10D)	OTOSRDJT	TR10D_HUMAN	Decreases Expression	[7]
Tumor necrosis factor ligand superfamily member 18 (TNFSF18)	OT3ANRX1	TNF18_HUMAN	Decreases Expression	[7]
TNF receptor-associated factor 6 (TRAF6)	OTA5GO5K	TRAF6_HUMAN	Increases Expression	[7]
------------------------------------------------------------------------------------


⏷ Show the Full List of 48 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: 7379).
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	Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
5	Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010 Aug;9(8):2344-53. doi: 10.1158/1535-7163.MCT-10-0324. Epub 2010 Jul 27.
6	CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep. 2016 Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077.
7	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.