Details of the Drug Combination

General Information of Drug Combination (ID: DCK4B6R)

• Drug Combination Name: 6-bromoindirubin-3-oxime + Ruxolitinib
• Indication: Hodgkin lymphoma; Status: Investigative [1]
• Component Drugs:
  6-bromoindirubin-3-oxime (DM12WYV): Small molecular drug
  Ruxolitinib (DM7Q98D): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: L-1236
  Zero Interaction Potency (ZIP) Score: 8.837
  Bliss Independence Score: 6.349
  Loewe Additivity Score: 8.471
  LHighest Single Agent (HSA) Score: 9.472

Molecular Interaction Atlas of This Drug Combination

Indication(s) of 6-bromoindirubin-3-oxime

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[2]

6-bromoindirubin-3-oxime Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glycogen synthase kinase-3 alpha (GSK-3A)	TTRZQE3	GSK3A_HUMAN	Inhibitor	[2]
Aurora B messenger RNA (AURKB mRNA)	TT9RTBL	AURKB_HUMAN	Inhibitor	[9]
Aurora kinase A (AURKA)	TTPS3C0	AURKA_HUMAN	Inhibitor	[9]
Aurora kinase C (AURKC)	TTLYXIT	AURKC_HUMAN	Inhibitor	[9]

6-bromoindirubin-3-oxime Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5)	OTMVHF9E	LGR5_HUMAN	Increases Expression	[10]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[10]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Expression	[11]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[11]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Increases Expression	[11]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Phosphorylation	[12]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Activity	[13]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[13]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Increases Expression	[11]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[11]

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	[14]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[14]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[15]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[16]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[16]

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	[17]

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] Stable generation of serum- and feeder-free embryonic stem cell-derived mice with full germline-competency by using a GSK3 specific inhibitor. Genesis. 2009 Jun;47(6):414-22.
• [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] An integrated computational approach to the phenomenon of potent and selective inhibition of aurora kinases B and C by a series of 7-substituted in... J Med Chem. 2007 Aug 23;50(17):4027-37.
• [10] Analysis of glycogen synthase kinase inhibitors that regulate cytochrome P450 expression in primary human hepatocytes by activation of beta-catenin, aryl hydrocarbon receptor and pregnane X receptor signaling. Toxicol Sci. 2015 Nov;148(1):261-75.
• [11] Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells. J Neurochem. 2008 Aug;106(4):1855-65. doi: 10.1111/j.1471-4159.2008.05537.x. Epub 2008 Jul 4.
• [12] A lentivirus-mediated genetic screen identifies dihydrofolate reductase (DHFR) as a modulator of beta-catenin/GSK3 signaling. PLoS One. 2009 Sep 3;4(9):e6892. doi: 10.1371/journal.pone.0006892.
• [13] GSK-3beta inhibition enhances sorafenib-induced apoptosis in melanoma cell lines. J Biol Chem. 2008 Jan 11;283(2):726-32. doi: 10.1074/jbc.M705343200. Epub 2007 Nov 8.
• [14] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [15] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [16] 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.
• [17] 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.