Details of the Drug Combination

General Information of Drug Combination (ID: DCER4MC)

• Drug Combination Name: Enzastaurin + Sunitinib
• Indication: Metastatic Renal Cell Carcinoma; Status: Phase 1 [1]
• Component Drugs:
  Enzastaurin (DM5H0R9): Small molecular drug
  Sunitinib (DMCBJSR): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Enzastaurin

Disease Entry	ICD 11	Status	REF
Diffuse large B-cell lymphoma	2A81	Phase 3	[2]
Non-hodgkin lymphoma	2B33.5	Phase 3	[3]
Glioblastoma multiforme	2A00.0	Phase 2	[3]
Central nervous system disease	8A04-8D87	Phase 1	[3]

Enzastaurin Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Protein kinase C beta (PRKCB)	TTYPXQF	KPCB_HUMAN	Modulator	[7]
RAC-alpha serine/threonine-protein kinase (AKT1)	TTWTSCV	AKT1_HUMAN	Inhibitor	[2]
PI3-kinase gamma (PIK3CG)	TTHBTOP	PK3CG_HUMAN	Inhibitor	[2]

Enzastaurin Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]

Indication(s) of Sunitinib

Disease Entry	ICD 11	Status	REF
Acute undifferentiated leukemia	N.A.	Approved	[4]
Chronic myelomonocytic leukemia	N.A.	Approved	[4]
Classic Kaposi sarcoma	N.A.	Approved	[4]
Gastrointestinal cancer	2C11	Approved	[5]
Gastrointestinal stromal tumour	2B5B	Approved	[6]
Large granular lymphocytic leukemia	2A90.1	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
Mast cell leukaemia	2A21.00	Approved	[4]
Non-small-cell lung cancer	2C25.Y	Approved	[4]
Pancreatic cancer	2C10	Approved	[4]
Primary myelofibrosis	2A20.2	Approved	[4]
Prolymphocytic leukaemia	2A82.1	Approved	[4]
Prostate adenocarcinoma	N.A.	Approved	[4]
Refractory chronic myeloid leukaemia	2A20	Approved	[4]
Salivary gland squamous cell carcinoma	N.A.	Approved	[4]
Plexiform neurofibroma	N.A.	Investigative	[4]

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	[9]

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	[10]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[12]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[12]
RalBP1-associated Eps domain-containing protein 2 (RALBP1)	DTYEM9B	REPS2_HUMAN	Substrate	[13]

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	[14]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[15]

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	[16]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases ADR	[17]

References

• [1] ClinicalTrials.gov (NCT00709995) A Study for Participants With Metastatic Renal Cell Carcinoma
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 5693).
• [4] Sunitinib FDA Label
• [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: 5713).
• [6] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [7] The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines. Leuk Lymphoma. 2008 Jul;49(7):1374-83.
• [8] Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics. Invest New Drugs. 2013 Jun;31(3):653-60.
• [9] 2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.
• [10] 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.
• [11] 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.
• [12] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [13] Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. Int J Cancer. 2010 Mar 15;126(6):1327-38.
• [14] 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.
• [15] Drug Interactions Flockhart Table
• [16] 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.
• [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.