Details of the Drug Combination

General Information of Drug Combination (ID: DCIQJHS)

• Drug Combination Name: Sunitinib + CONTIGOSIDE B
• Indication: Renal Cell Carcinoma; Status: Phase 1 [1]
• Component Drugs:
  Sunitinib (DMCBJSR): Small molecular drug
  CONTIGOSIDE B (DMX9V8K): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sunitinib

Disease Entry	ICD 11	Status	REF
Acute undifferentiated leukemia	N.A.	Approved	[2]
Chronic myelomonocytic leukemia	N.A.	Approved	[2]
Classic Kaposi sarcoma	N.A.	Approved	[2]
Gastrointestinal cancer	2C11	Approved	[3]
Gastrointestinal stromal tumour	2B5B	Approved	[4]
Large granular lymphocytic leukemia	2A90.1	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Mast cell leukaemia	2A21.00	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Pancreatic cancer	2C10	Approved	[2]
Primary myelofibrosis	2A20.2	Approved	[2]
Prolymphocytic leukaemia	2A82.1	Approved	[2]
Prostate adenocarcinoma	N.A.	Approved	[2]
Refractory chronic myeloid leukaemia	2A20	Approved	[2]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Plexiform neurofibroma	N.A.	Investigative	[2]

Sunitinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Modulator	[6]

Sunitinib Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[9]
RalBP1-associated Eps domain-containing protein 2 (RALBP1)	DTYEM9B	REPS2_HUMAN	Substrate	[10]

Sunitinib Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[12]

Sunitinib Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases ADR	[13]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases ADR	[14]

Indication(s) of CONTIGOSIDE B

Disease Entry	ICD 11	Status	REF
Thrombosis	DB61-GB90	Phase 2/3	[5]

CONTIGOSIDE B Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aldose reductase (AKR1B1)	TTFBNVI	ALDR_HUMAN	Inhibitor	[16]
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[17]

CONTIGOSIDE B Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Beta-glucosidase (bglA)	DEXLYGD	Q9ZNN7_BACSP	Metabolism	[18]
Beta-glucosidase (bglA)	DEZXOEW	R5RU84_9BACE	Metabolism	[18]
Beta-glucosidase (bglA)	DE4WCJL	R5RU84_9BACE	Metabolism	[18]

CONTIGOSIDE B Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[19]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[19]
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Increases Expression	[15]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Increases Expression	[20]
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Increases Secretion	[21]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[15]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[15]
Tyrosine-protein kinase JAK1 (JAK1)	OT0X3D17	JAK1_HUMAN	Increases Expression	[15]
Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1)	OT5BZ1J9	P85A_HUMAN	Increases Expression	[15]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Affects Expression	[15]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Increases Expression	[15]
Signal transducer and activator of transcription 6 (STAT6)	OTCKMP49	STAT6_HUMAN	Increases Expression	[15]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Affects Expression	[15]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Affects Expression	[15]
Transcription factor RelB (RELB)	OTU3QYEF	RELB_HUMAN	Increases Expression	[15]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Affects Expression	[15]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Decreases Expression	[15]

References

• [1] ClinicalTrials.gov (NCT02446795) Isoquercetin as an Adjunct Therapy in Patients With Kidney Cancer Receiving First-line Sunitinib: a Phase I/II Trial
• [2] Sunitinib FDA Label
• [3] 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: 5713).
• [4] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] 2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.
• [7] Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9.
• [8] Double-transduced MDCKII cells to study human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) interplay in drug transport across the blood-brain barrier. Mol Pharm. 2011 Apr 4;8(2):571-82.
• [9] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [10] Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. Int J Cancer. 2010 Mar 15;126(6):1327-38.
• [11] In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9.
• [12] Drug Interactions Flockhart Table
• [13] Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma. Pharmacogenomics J. 2017 Jan;17(1):42-46. doi: 10.1038/tpj.2015.100. Epub 2016 Jan 26.
• [14] 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.
• [15] Improved Preventive Effects of Combined Bioactive Compounds Present in Different Blueberry Varieties as Compared to Single Phytochemicals. Nutrients. 2018 Dec 29;11(1):61. doi: 10.3390/nu11010061.
• [16] Effect of Polygonum hydropiper sulfated flavonoids on lens aldose reductase and related enzymes. J Nat Prod. 1996 Apr;59(4):443-5.
• [17] Inhibitory effects of various flavonoids isolated from leaves of persimmon on angiotensin-converting enzyme activity. J Nat Prod. 1987 Jul-Aug;50(4):680-3.
• [18] Identification of rutin deglycosylated metabolites produced by human intestinal bacteria using UPLC-Q-TOF/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Jun 1;898:95-100.
• [19] Inhibition of human cytochrome CYP 1 enzymes by flavonoids of StJohn's wort. Toxicology. 2006 Jan 16;217(2-3):194-205.
• [20] Flavonoid glycosides isolated from Salicornia herbacea inhibit matrix metalloproteinase in HT1080 cells. Toxicol In Vitro. 2008 Oct;22(7):1742-8. doi: 10.1016/j.tiv.2008.07.013. Epub 2008 Jul 31.
• [21] Induction of hepatic apolipoprotein A-I gene expression by the isoflavones quercetin and isoquercetrin. Life Sci. 2014 Aug 6;110(1):8-14. doi: 10.1016/j.lfs.2014.06.014. Epub 2014 Jun 22.