Details of the Drug Combination

General Information of Drug Combination (ID: DCI68CB)

• Drug Combination Name: Riboflavin + Ruxolitinib
• Indication: Hodgkin lymphoma; Status: Investigative [1]
• Component Drugs:
  Riboflavin (DM8YMWE): Small molecular drug
  Ruxolitinib (DM7Q98D): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: L-1236
  Zero Interaction Potency (ZIP) Score: 8.47
  Bliss Independence Score: 12.732
  Loewe Additivity Score: 1.439
  LHighest Single Agent (HSA) Score: 8.968

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Riboflavin

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[2]
Vitamin deficiency	5B55-5B71	Approved	[3]

Riboflavin Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]
Riboflavin transporter 1 (SLC52A1)	DT7NOKR	S52A1_HUMAN	Substrate	[11]
Riboflavin transporter 3 (SLC52A2)	DTAVOS6	S52A2_HUMAN	Substrate	[11]
Riboflavin transporter 2 (SLC52A3)	DTBVQIO	S52A3_HUMAN	Substrate	[11]

Riboflavin Interacts with 10 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[12]
Testicular acid phosphatase (ACP4)	DE3OZT4	PPAT_HUMAN	Metabolism	[13]
Tartrate-resistant acid ATPase (ACP5)	DESITDW	PPA5_HUMAN	Metabolism	[13]
Acid phosphatase-like protein 1 (ACP6)	DER6BCE	PPA6_HUMAN	Metabolism	[13]
Prostatic acid phosphatase (ACP3)	DEDW5H6	PPAP_HUMAN	Metabolism	[13]
Eosinophil peroxidase (EPX)	DETE84Z	PERE_HUMAN	Metabolism	[13]
Xylosyl phosphatase (PXYLP1)	DEGSUI0	PXYP1_HUMAN	Metabolism	[13]
NADPH-dependent oxidoreductase (nfrA)	DE82GV7	NRFA_STAA8	Metabolism	[14]
NADPH-dependent nitroreductase (nfrA1)	DE21PLI	NFRA1_BACSU	Metabolism	[15]
Nitroreductase (NTR)	DE0K82S	A0A5K1UB29_SALTM	Metabolism	[16]

Riboflavin Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Affects Expression	[17]
Glutathione reductase, mitochondrial (GSR)	OTM2TUYM	GSHR_HUMAN	Affects Expression	[18]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[19]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[19]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[19]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Affects Expression	[17]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Affects Expression	[18]
Kinesin-like protein KIF23 (KIF23)	OTY850JC	KIF23_HUMAN	Affects Expression	[17]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[19]
Abnormal spindle-like microcephaly-associated protein (ASPM)	OTKXQMNA	ASPM_HUMAN	Affects Expression	[17]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Increases Expression	[20]
Zinc finger protein PLAGL1 (PLAGL1)	OTZAO900	PLAL1_HUMAN	Affects Expression	[18]
Methylenetetrahydrofolate reductase (MTHFR)	OTUBJSR7	MTHR_HUMAN	Affects Response To Substance	[21]

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[4]
High-risk myelofibrosis	2A20.2	Approved	[5]
Myelofibrosis	2A22	Approved	[6]
Myeloproliferative neoplasm	2A20	Approved	[7]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[8]
Pancreatic cancer	2C10	Phase 3	[5]
Atopic dermatitis	EA80	Phase 1/2	[9]
Vitiligo	ED63.0	Phase 1/2	[9]

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	[22]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[22]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[23]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[24]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[24]

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	[25]

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] 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: 6578).
• [3] Riboflavin FDA Label
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] 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).
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] Ruxolitinib FDA Label
• [8] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol. 2007 Feb;27(4):1247-53.
• [11] An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Mol Genet Metab. 2017 Dec;122(4):182-188.
• [12] Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone. Biochem J. 1998 Apr 1;331 ( Pt 1):273-81.
• [13] An atlas of human metabolism. Sci Signal. 2020 Mar 24;13(624). pii: eaaz1482. (Reaction HMR_6507)
• [14] Reduction of polynitroaromatic compounds: the bacterial nitroreductases. FEMS Microbiol Rev. 2008 May;32(3):474-500.
• [15] Conversion of NfsA, the major Escherichia coli nitroreductase, to a flavin reductase with an activity similar to that of Frp, a flavin reductase in Vibrio harveyi, by a single amino acid substitution. J Bacteriol. 1998 Jan;180(2):422-5.
• [16] Purification and characterization of wild-type and mutant "classical" nitroreductases of Salmonella typhimurium. L33R mutation greatly diminishes binding of FMN to the nitroreductase of S. typhimurium. J Biol Chem. 1998 Sep 11;273(37):23922-8.
• [17] Riboflavin depletion impairs cell proliferation in adult human duodenum: identification of potential effectors. Dig Dis Sci. 2011 Apr;56(4):1007-19. doi: 10.1007/s10620-010-1374-3. Epub 2010 Sep 17.
• [18] Riboflavin deficiency causes protein and DNA damage in HepG2 cells, triggering arrest in G1 phase of the cell cycle. J Nutr Biochem. 2006 Apr;17(4):250-6. doi: 10.1016/j.jnutbio.2005.05.004. Epub 2005 Jun 13.
• [19] [Apoptosis of human gastric cancer cell induced by photochemical riboflavin]. Ai Zheng. 2003 Mar;22(3):253-6.
• [20] A cardiac-specific robotized cellular assay identified families of human ligands as inducers of PGC-1 expression and mitochondrial biogenesis. PLoS One. 2012;7(10):e46753. doi: 10.1371/journal.pone.0046753. Epub 2012 Oct 3.
• [21] Protective association of MTHFR polymorphism on cervical intraepithelial neoplasia is modified by riboflavin status. Nutrition. 2007 Mar;23(3):229-35. doi: 10.1016/j.nut.2006.12.006. Epub 2007 Feb 14.
• [22] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [23] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [24] 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.
• [25] 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.