Details of the Drug Combination

General Information of Drug Combination (ID: DCUDI3Z)

• Drug Combination Name: CHIR-99021 + Ruxolitinib
• Indication: Hodgkin lymphoma; Status: Investigative [1]
• Component Drugs:
  CHIR-99021 (DMB8MNU): Small molecular drug
  Ruxolitinib (DM7Q98D): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: L-1236
  Zero Interaction Potency (ZIP) Score: 15.243
  Bliss Independence Score: 15.032
  Loewe Additivity Score: 3.748
  LHighest Single Agent (HSA) Score: 4.938

Molecular Interaction Atlas of This Drug Combination

Indication(s) of CHIR-99021

Disease Entry	ICD 11	Status	REF
Allergic inflammation	4A80-4A85	Patented	[2]
Graft rejection	NE84	Patented	[2]

CHIR-99021 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	[10]
Extracellular signal-regulated kinase 2 (ERK2)	TT4TQBX	MK01_HUMAN	Inhibitor	[10]
Glycogen synthase kinase-3 beta (GSK-3B)	TTRSMW9	GSK3B_HUMAN	Inhibitor	[10]
Glycogen synthase kinase-3 alpha (GSK-3A)	TTRZQE3	GSK3A_HUMAN	Inhibitor	[2]

CHIR-99021 Interacts with 26 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Affects Phosphorylation	[11]
Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5)	OTMVHF9E	LGR5_HUMAN	Increases Expression	[12]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[12]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Expression	[12]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[12]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Increases Expression	[12]
Mesogenin-1 (MSGN1)	OTZGNRKZ	MSGN1_HUMAN	Increases Expression	[9]
T-box transcription factor TBX6 (TBX6)	OTW1Q8RM	TBX6_HUMAN	Increases Expression	[9]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[13]
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Increases Expression	[9]
Alpha-fetoprotein (AFP)	OT9GG3ZI	FETA_HUMAN	Increases Expression	[9]
Homeobox protein Hox-B7 (HOXB7)	OTC7WYU8	HXB7_HUMAN	Increases Expression	[9]
Paired box protein Pax-6 (PAX6)	OTOC9876	PAX6_HUMAN	Increases Expression	[9]
Homeobox protein CDX-1 (CDX1)	OTOHTMJE	CDX1_HUMAN	Increases Expression	[9]
Transcription factor SOX-2 (SOX2)	OTFAWCAU	SOX2_HUMAN	Decreases Expression	[9]
Fibroblast growth factor 8 (FGF8)	OTFU0IUW	FGF8_HUMAN	Increases Expression	[9]
Hepatocyte nuclear factor 3-alpha (FOXA1)	OTEBY0TD	FOXA1_HUMAN	Increases Expression	[9]
55 kDa erythrocyte membrane protein (MPP1)	OTA2ENZQ	EM55_HUMAN	Increases Expression	[9]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Decreases Expression	[9]
Indian hedgehog protein (IHH)	OT1DWGXC	IHH_HUMAN	Increases Expression	[9]
Rapamycin-insensitive companion of mTOR (RICTOR)	OTCC58QJ	RICTR_HUMAN	Increases Expression	[13]
Transcription factor GATA-6 (GATA6)	OTO2BC0F	GATA6_HUMAN	Increases Expression	[9]
Nodal homolog (NODAL)	OTZ34981	NODAL_HUMAN	Increases Expression	[9]
Transcription factor HES-7 (HES7)	OT6F9R7P	HES7_HUMAN	Increases Expression	[9]
Transcription factor SOX-17 (SOX17)	OT9H4WWE	SOX17_HUMAN	Increases Expression	[9]
Homeobox protein NANOG (NANOG)	OTUEY1FM	NANOG_HUMAN	Decreases 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	[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] Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015).Expert Opin Ther Pat. 2017 Jun;27(6):657-666.
• [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] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [10] Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes. 2003 Mar;52(3):588-95.
• [11] Cytoplasmic aryl hydrocarbon receptor regulates glycogen synthase kinase 3 beta, accelerates vimentin degradation, and suppresses epithelial-mesenchymal transition in non-small cell lung cancer cells. Arch Toxicol. 2017 May;91(5):2165-2178.
• [12] 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.
• [13] Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation. J Biol Chem. 2015 May 29;290(22):14120-9. doi: 10.1074/jbc.M114.633057. Epub 2015 Apr 20.
• [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.