Details of the Drug Combination

General Information of Drug Combination (ID: DC1W4ZZ)

• Drug Combination Name: URSOLIC ACID + Ruxolitinib
• Indication: Hodgkin lymphoma; Status: Investigative [1]
• Component Drugs:
  URSOLIC ACID (DM4SOAW): Small molecular drug
  Ruxolitinib (DM7Q98D): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: L-1236
  Zero Interaction Potency (ZIP) Score: 2.815
  Bliss Independence Score: 2.649
  Loewe Additivity Score: 10.966
  LHighest Single Agent (HSA) Score: 12.967

Molecular Interaction Atlas of This Drug Combination

Indication(s) of URSOLIC ACID

Disease Entry	ICD 11	Status	REF
Metabolic syndrome x	5C50-5D2Z	Phase 2	[2]

URSOLIC ACID Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phospholipase A2 (PLA2G1B)	TT9V5JH	PA21B_HUMAN	Inhibitor	[9]
Herpes simplex virus DNA polymerase UL30 (HSV UL30)	TTIU7X1	DPOL_HHV11	Inhibitor	[10]
Corticosteroid 11-beta-dehydrogenase 1 (HSD11B1)	TTN7BL9	DHI1_HUMAN	Inhibitor	[11]
PTPN1 messenger RNA (PTPN1 mRNA)	TTELIN2	PTN1_HUMAN	Inhibitor	[12]
Glycogen phosphorylase muscle form (GP)	TTZHY6R	PYGM_HUMAN	Inhibitor	[13]

URSOLIC ACID Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[14]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Activity	[15]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[16]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[15]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[17]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[18]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[15]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[15]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[15]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[15]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[18]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[19]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Phosphorylation	[15]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Activity	[20]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Phosphorylation	[15]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Decreases Response To Substance	[20]

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	[21]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[21]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[22]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[23]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[23]

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	[24]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] ClinicalTrials.gov (NCT02337933) Effect of Ursolic Acid Administration on Insulin Sensitivity and Metabolic Syndrome. U.S. National Institutes of Health.
• [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] Synthesis of benzoyl phenyl benzoates as effective inhibitors for phospholipase A2 and hyaluronidase enzymes. Bioorg Med Chem Lett. 2005 Sep 15;15(18):4100-4.
• [10] DNA polymerase beta inhibitors from Baeckea gunniana. J Nat Prod. 1999 Dec;62(12):1624-6.
• [11] 11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational a... Bioorg Med Chem. 2010 Feb 15;18(4):1507-15.
• [12] Cytotoxic and PTP1B inhibitory activities from Erythrina abyssinica. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6745-9.
• [13] Synthesis of 3-deoxypentacyclic triterpene derivatives as inhibitors of glycogen phosphorylase. J Nat Prod. 2009 Aug;72(8):1414-8.
• [14] Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes. Life Sci. 2004 Apr 16;74(22):2769-79.
• [15] Ursolic acid induces autophagy in U87MG cells via ROS-dependent endoplasmic reticulum stress. Chem Biol Interact. 2014 Jul 25;218:28-41. doi: 10.1016/j.cbi.2014.04.017. Epub 2014 May 5.
• [16] Inhibition of cell proliferation, invasion and migration by ursolic acid in human lung cancer cell lines. Toxicol In Vitro. 2011 Oct;25(7):1274-80. doi: 10.1016/j.tiv.2011.04.014. Epub 2011 Apr 20.
• [17] Ursolic acid reduces Adriamycin resistance of human ovarian cancer cells through promoting the HuR translocation from cytoplasm to nucleus. Environ Toxicol. 2021 Feb;36(2):267-275. doi: 10.1002/tox.23032. Epub 2020 Oct 3.
• [18] Molecular mechanism of ursolic acid induced apoptosis in poorly differentiated endometrial cancer HEC108 cells. Oncol Rep. 2005 Aug;14(2):507-12.
• [19] 2, 3, 23-trihydroxy-urs-12-ene-28-olic acid (TUA) isolated from Actinidia chinensis Radix inhibits NCI-H460 cell proliferation by decreasing NF-B expression. Chem Biol Interact. 2015 Oct 5;240:1-11. doi: 10.1016/j.cbi.2015.06.038. Epub 2015 Jun 30.
• [20] Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor. Cancer Lett. 2010 Dec 1;298(1):128-38. doi: 10.1016/j.canlet.2010.06.010. Epub 2010 Jul 13.
• [21] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [22] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [23] 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.
• [24] 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.