Details of the Drug Combination

General Information of Drug Combination (ID: DCNTHLC)

• Drug Combination Name: Enzastaurin + Erlotinib
• Indication: Non-Small Cell Lung Cancer; Status: Phase 1 [1]
• Component Drugs:
  Enzastaurin (DM5H0R9): Small molecular drug
  Erlotinib (DMCMBHA): 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	[6]
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	[7]

Indication(s) of Erlotinib

Disease Entry	ICD 11	Status	REF
Adrenal gland neoplasm	N.A.	Approved	[4]
Adult hepatocellular carcinoma	N.A.	Approved	[4]
Brain cancer	2A00	Approved	[4]
Esophageal disorder	N.A.	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
Non-small-cell lung cancer	2C25.Y	Approved	[5]
Pancreatic adenocarcinoma	N.A.	Approved	[4]
Psoriasis	EA90	Approved	[4]
Salivary gland squamous cell carcinoma	N.A.	Approved	[4]
Pancreatic cancer	2C10	Phase 3	[5]
Colon cancer	2B90.Z	Phase 2	[5]
Ependymoma	2A00.0Y	Investigative	[4]
Neoplastic meningitis	N.A.	Investigative	[4]
Neuroblastoma	2D11.2	Investigative	[4]

Erlotinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[8]

Erlotinib Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]

Erlotinib Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]

Erlotinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Response	[13]

References

• [1] ClinicalTrials.gov (NCT00452413) A Study of Enzastaurin and Erlotinib in Participants With Solid Tumors and Lung Cancer
• [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] Erlotinib 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: 4920).
• [6] 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.
• [7] 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.
• [8] Quantitative prediction of fold resistance for inhibitors of EGFR. Biochemistry. 2009 Sep 8;48(35):8435-48.
• [9] Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice. Mol Cancer Ther. 2008 Aug;7(8):2280-7.
• [10] Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33.
• [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] Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
• [13] Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 Apr 29.