Details of the Drug Combination

General Information of Drug Combination (ID: DCVGMZ8)

• Drug Combination Name: R-roscovitine + Ruxolitinib
• Indication: T-cell leukemia/lymphoma; Status: Investigative [1]
• Component Drugs:
  R-roscovitine (DMSH108): Small molecular drug
  Ruxolitinib (DM7Q98D): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: ED-40515
  Zero Interaction Potency (ZIP) Score: 1.228
  Bliss Independence Score: 3.717
  Loewe Additivity Score: 1.641
  LHighest Single Agent (HSA) Score: 3.827

Molecular Interaction Atlas of This Drug Combination

Indication(s) of R-roscovitine

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Phase 2	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[3]
Nasopharyngeal carcinoma	2B6B	Investigative	[4]

R-roscovitine Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[12]
Cyclin-dependent kinase 7 (CDK7)	TTQYF7G	CDK7_HUMAN	Inhibitor	[12]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[12]
Cyclin-dependent kinase (CDK)	TTMBO1Z	NOUNIPROTAC	Inhibitor	[4]

R-roscovitine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]

R-roscovitine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[14]

R-roscovitine Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[15]
Early growth response protein 1 (EGR1)	OTCP6XGZ	EGR1_HUMAN	Decreases Expression	[16]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[17]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Increases Expression	[18]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Increases Expression	[18]
DNA topoisomerase 1 (TOP1)	OT51O0CF	TOP1_HUMAN	Increases Expression	[19]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[20]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[21]
Retinoblastoma-like protein 1 (RBL1)	OTDEBFYC	RBL1_HUMAN	Decreases Expression	[20]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Affects Expression	[21]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[11]
Casein kinase I isoform delta (CSNK1D)	OTNF4S77	KC1D_HUMAN	Decreases Activity	[22]
Serine/threonine-protein kinase PLK1 (PLK1)	OTRZX45T	PLK1_HUMAN	Decreases Expression	[20]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[11]
Disabled homolog 2 (DAB2)	OTRMQTMZ	DAB2_HUMAN	Decreases Phosphorylation	[23]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[11]
Cyclin-dependent kinase 5 (CDK5)	OT1YAK9F	CDK5_HUMAN	Decreases Activity	[24]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[17]
Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)	OTPLXCDN	DYR1A_HUMAN	Decreases Activity	[22]

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[5]
High-risk myelofibrosis	2A20.2	Approved	[6]
Myelofibrosis	2A22	Approved	[7]
Myeloproliferative neoplasm	2A20	Approved	[8]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[9]
Pancreatic cancer	2C10	Phase 3	[6]
Atopic dermatitis	EA80	Phase 1/2	[10]
Vitiligo	ED63.0	Phase 1/2	[10]

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	[25]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[25]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[26]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[27]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[27]

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	[28]

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: 6035).
• [3] ClinicalTrials.gov (NCT02160730) Treatment of Cushing's Disease With R-roscovitine. U.S. National Institutes of Health.
• [4] Therapeutic efficacy of seliciclib in combination with ionizing radiation for human nasopharyngeal carcinoma.Clin Cancer Res. 2009 Jun 1;15(11):3716-24.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] 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).
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [8] Ruxolitinib FDA Label
• [9] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [10] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [11] Accumulation of p53 and reductions in XIAP abundance promote the apoptosis of prostate cancer cells. Cancer Res. 2005 Sep 1;65(17):7717-23. doi: 10.1158/0008-5472.CAN-05-0347.
• [12] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [13] ATP-binding cassette B1 transports seliciclib (R-roscovitine), a cyclin-dependent kinase inhibitor. Drug Metab Dispos. 2010 Nov;38(11):2000-6.
• [14] Metabolism of the trisubstituted purine cyclin-dependent kinase inhibitor seliciclib (R-roscovitine) in vitro and in vivo. Drug Metab Dispos. 2008 Mar;36(3):561-70.
• [15] Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor. Cell Mol Life Sci. 2005 Aug;62(15):1763-71.
• [16] Aryl hydrocarbon receptor-dependent up-regulation of the heterodimeric amino acid transporter LAT1 (SLC7A5)/CD98hc (SLC3A2) by diesel exhaust particle extract in human bronchial epithelial cells. Toxicol Appl Pharmacol. 2016 Jan 1;290:74-85.
• [17] Roscovitine is an effective inducer of apoptosis of Ewing's sarcoma family tumor cells in vitro and in vivo. Cancer Res. 2005 Oct 15;65(20):9320-7. doi: 10.1158/0008-5472.CAN-05-1276.
• [18] The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin-dependent kinase inhibitors. Eur J Biochem. 2003 Dec;270(24):4809-22. doi: 10.1046/j.1432-1033.2003.03874.x.
• [19] Synergism of cyclin-dependent kinase inhibitors with camptothecin derivatives in small cell lung cancer cell lines. Molecules. 2014 Feb 17;19(2):2077-88. doi: 10.3390/molecules19022077.
• [20] Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology. 2010 May;138(5):1920-30. doi: 10.1053/j.gastro.2010.01.007. Epub 2010 Jan 25.
• [21] A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer. Oncogene. 2011 Apr 28;30(17):2026-36. doi: 10.1038/onc.2010.578. Epub 2011 Jan 10.
• [22] The specificities of protein kinase inhibitors: an update. Biochem J. 2003 Apr 1;371(Pt 1):199-204. doi: 10.1042/BJ20021535.
• [23] Cell cycle-dependent phosphorylation of Disabled-2 by cdc2. Oncogene. 2003 Jul 17;22(29):4524-30. doi: 10.1038/sj.onc.1206767.
• [24] p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death. J Cell Sci. 2005 Mar 15;118(Pt 6):1291-8. doi: 10.1242/jcs.01724. Epub 2005 Mar 1.
• [25] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [26] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [27] 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.
• [28] 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.