Details of the Drug Combination

General Information of Drug Combination (ID: DCL4ERT)

• Drug Combination Name: PF-3758309 + Ruxolitinib
• Indication: Hodgkin lymphoma; Status: Investigative [1]
• Component Drugs:
  PF-3758309 (DM36PKZ): Small molecular drug
  Ruxolitinib (DM7Q98D): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: L-1236
  Zero Interaction Potency (ZIP) Score: 2.1
  Bliss Independence Score: 2.47
  Loewe Additivity Score: 8.01
  LHighest Single Agent (HSA) Score: 9

Molecular Interaction Atlas of This Drug Combination

Indication(s) of PF-3758309

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

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	[2]

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	[9]
Suppressor of cytokine signaling 3 (SOCS3)	OTY183WJ	SOCS3_HUMAN	Decreases Expression	[9]
T-box transcription factor TBX3 (TBX3)	OTM64N7K	TBX3_HUMAN	Increases Expression	[9]
Receptor-interacting serine/threonine-protein kinase 2 (RIPK2)	OT0KMIYQ	RIPK2_HUMAN	Decreases Expression	[9]
Tumor necrosis factor ligand superfamily member 14 (TNFSF14)	OT5QRF09	TNF14_HUMAN	Increases Expression	[9]
Nucleolar protein 3 (NOL3)	OT1K0L0D	NOL3_HUMAN	Increases Expression	[9]
STAM-binding protein (STAMBP)	OTOT2OXM	STABP_HUMAN	Decreases Expression	[9]
Interferon alpha-2 (IFNA2)	OT4GII73	IFNA2_HUMAN	Increases Expression	[9]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[9]
Alpha-crystallin B chain (CRYAB)	OTY4JGYU	CRYAB_HUMAN	Increases Expression	[9]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[9]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[9]
CCAAT/enhancer-binding protein beta (CEBPB)	OTM9MQIA	CEBPB_HUMAN	Decreases Expression	[9]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[9]
Azurocidin (AZU1)	OTHXU264	CAP7_HUMAN	Decreases Expression	[9]
Brain-derived neurotrophic factor (BDNF)	OTLGH7EW	BDNF_HUMAN	Increases Expression	[9]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[9]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[9]
Caspase-1 (CASP1)	OTZ3YQFU	CASP1_HUMAN	Decreases Expression	[9]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Increases Expression	[9]
Tumor necrosis factor ligand superfamily member 8 (TNFSF8)	OTDYGDJ3	TNFL8_HUMAN	Decreases Expression	[9]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[9]
B-cell lymphoma 6 protein (BCL6)	OTQAWWO1	BCL6_HUMAN	Increases Expression	[9]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Decreases Expression	[9]
Protein kinase C zeta type (PRKCZ)	OTN2FE42	KPCZ_HUMAN	Increases Expression	[9]
Elongation factor 1-alpha 2 (EEF1A2)	OT9Z23K5	EF1A2_HUMAN	Increases Expression	[9]
Lymphotoxin-beta (LTB)	OTUFS8CF	TNFC_HUMAN	Increases Expression	[9]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Decreases Expression	[9]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[9]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[9]
C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2)	OTDUHLN0	JIP2_HUMAN	Increases Expression	[9]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[9]
Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD)	OTBOSJHO	TRADD_HUMAN	Increases Expression	[9]
Bcl-2-related protein A1 (BCL2A1)	OTWRYSNA	B2LA1_HUMAN	Decreases Expression	[9]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[9]
Gamma-interferon-inducible protein 16 (IFI16)	OT4SPU0U	IF16_HUMAN	Decreases Expression	[9]
Quinone oxidoreductase PIG3 (TP53I3)	OTSCM68G	QORX_HUMAN	Increases Expression	[9]
Ectodysplasin-A (EDA)	OTAKS5WS	EDA_HUMAN	Increases Expression	[9]
Bcl-2-like protein 2 (BCL2L2)	OTMKVO0J	B2CL2_HUMAN	Increases Expression	[9]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[9]
Homeobox protein Nkx-3.1 (NKX3-1)	OT0DO6ZU	NKX31_HUMAN	Increases Expression	[9]
Caspase recruitment domain-containing protein 6 (CARD6)	OTEI1PJ1	CARD6_HUMAN	Decreases Expression	[9]
Protein AATF (AATF)	OT1QOKLD	AATF_HUMAN	Decreases Expression	[9]
Bcl-2-associated transcription factor 1 (BCLAF1)	OT7T8H6A	BCLF1_HUMAN	Decreases Expression	[9]
Serine/threonine-protein kinase pim-2 (PIM2)	OTHQGU3I	PIM2_HUMAN	Decreases Expression	[9]
Tumor necrosis factor receptor superfamily member 10D (TNFRSF10D)	OTOSRDJT	TR10D_HUMAN	Decreases Expression	[9]
Tumor necrosis factor ligand superfamily member 18 (TNFSF18)	OT3ANRX1	TNF18_HUMAN	Decreases Expression	[9]
TNF receptor-associated factor 6 (TRAF6)	OTA5GO5K	TRAF6_HUMAN	Increases Expression	[9]

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[3]
High-risk myelofibrosis	2A20.2	Approved	[4]
Myelofibrosis	2A22	Approved	[5]
Myeloproliferative neoplasm	2A20	Approved	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[7]
Pancreatic cancer	2C10	Phase 3	[4]
Atopic dermatitis	EA80	Phase 1/2	[8]
Vitiligo	ED63.0	Phase 1/2	[8]

Ruxolitinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Janus kinase 2 (JAK-2)	TTRMX3V	JAK2_HUMAN	Modulator	[10]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[10]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[11]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[12]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[12]

Ruxolitinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Mitogen-activated protein kinase 14 (MAPK14)	OT5TCO3O	MK14_HUMAN	Increases ADR	[13]

References

• [1] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
• [2] 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.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 5688).
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Ruxolitinib FDA Label
• [7] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] 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.
• [10] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [11] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [12] The Use of Anti-Inflammatory Drugs in the Treatment of People With Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists From China. Clin Immunol. 2020 May;214:108393.
• [13] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.