Details of the Drug Combination

General Information of Drug Combination (ID: DC1TDPF)

• Drug Combination Name: ABT-737 + Ruxolitinib
• Indication: Hodgkin lymphoma; Status: Investigative [1]
• Component Drugs:
  ABT-737 (DML0DBV): Small molecular drug
  Ruxolitinib (DM7Q98D): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: L-1236
  Zero Interaction Potency (ZIP) Score: 13.49
  Bliss Independence Score: 12.44
  Loewe Additivity Score: 2.25
  LHighest Single Agent (HSA) Score: 5.02

Molecular Interaction Atlas of This Drug Combination

ABT-737 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-2 (BCL-2)	TTJGNVC	BCL2_HUMAN	Inhibitor	[8]

ABT-737 Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

ABT-737 Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Response To Substance	[10]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[11]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[12]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[11]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[13]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Folding	[10]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[14]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[15]
Homeobox protein NANOG (NANOG)	OTUEY1FM	NANOG_HUMAN	Decreases Expression	[16]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Response To Substance	[10]
BAG family molecular chaperone regulator 3 (BAG3)	OTVXYUDQ	BAG3_HUMAN	Decreases Response To Substance	[17]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Response To Substance	[18]

Indication(s) of Ruxolitinib

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

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	[19]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[19]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[20]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[21]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[21]

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	[22]

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] 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: 5688).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Ruxolitinib FDA Label
• [6] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem. 2007 Feb 22;50(4):641-62.
• [9] The B-cell lymphoma 2 (BCL2)-inhibitors, ABT-737 and ABT-263, are substrates for P-glycoprotein. Biochem Biophys Res Commun. 2011 May 6;408(2):344-9.
• [10] Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006 Nov;10(5):375-88. doi: 10.1016/j.ccr.2006.10.006.
• [11] The Bcl-2 homology domain 3 mimetic ABT-737 targets the apoptotic machinery in acute lymphoblastic leukemia resulting in synergistic in vitro and in vivo interactions with established drugs. Mol Pharmacol. 2010 Mar;77(3):483-94. doi: 10.1124/mol.109.060780. Epub 2009 Dec 28.
• [12] Combined Bcl-2/mammalian target of rapamycin inhibition leads to enhanced radiosensitization via induction of apoptosis and autophagy in non-small cell lung tumor xenograft model. Clin Cancer Res. 2009 Oct 1;15(19):6096-105. doi: 10.1158/1078-0432.CCR-09-0589. Epub 2009 Sep 22.
• [13] Para-tertiary butyl catechol (PTBC), an industrial antioxidant induces human platelet apoptosis. Environ Toxicol. 2019 Mar;34(3):262-270. doi: 10.1002/tox.22681. Epub 2018 Nov 21.
• [14] Apoptosis induces Bcl-XS and cleaved Bcl-XL in chronic lymphocytic leukaemia. Biochem Biophys Res Commun. 2011 Feb 18;405(3):480-5. doi: 10.1016/j.bbrc.2011.01.057. Epub 2011 Jan 20.
• [15] Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells. Autophagy. 2010 Feb;6(2):256-69. doi: 10.4161/auto.6.2.11124. Epub 2010 Feb 6.
• [16] Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):E3281-90. doi: 10.1073/pnas.1303669110. Epub 2013 Aug 5.
• [17] The stress protein BAG3 stabilizes Mcl-1 protein and promotes survival of cancer cells and resistance to antagonist ABT-737. J Biol Chem. 2013 Mar 8;288(10):6980-90. doi: 10.1074/jbc.M112.414177. Epub 2013 Jan 22.
• [18] Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer. Int J Cancer. 2007 Dec 1;121(11):2387-94. doi: 10.1002/ijc.22977.
• [19] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [20] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [21] 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.
• [22] 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.