Details of the Drug Combination

General Information of Drug Combination (ID: DC7E9KT)

• Drug Combination Name: HKI-272 + Vinorelbine
• Indication: Breast Cancer; Status: Phase 1 [1]
• Component Drugs:
  HKI-272 (DM6QOVN): Small molecular drug
  Vinorelbine (DMVXFYE): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of HKI-272

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 3	[2]

HKI-272 Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[5]
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[6]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[6]
ERBB2 messenger RNA (HER2 mRNA)	TTR5TV4	ERBB2_HUMAN	Inhibitor	[7]

HKI-272 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]

HKI-272 Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[9]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Expression	[10]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Activity	[11]

Indication(s) of Vinorelbine

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[3]
Lung cancer	2C25.0	Approved	[3]
Non-small-cell lung cancer	2C25.Y	Approved	[3]
Solid tumour/cancer	2A00-2F9Z	Approved	[4]

Vinorelbine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin (TUB)	TTML2WA	NOUNIPROTAC	Inhibitor	[12]

Vinorelbine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]

Vinorelbine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[15]

Vinorelbine Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[16]
Cyclin-dependent kinase inhibitor 2A (CDKN2A)	OTN0ZWAE	CDN2A_HUMAN	Decreases Expression	[16]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[17]
Vitamin K-dependent protein C (PROC)	OTGVH484	PROC_HUMAN	Decreases Expression	[18]
Keratin, type I cytoskeletal 18 (KRT18)	OTVLQFIP	K1C18_HUMAN	Increases Expression	[19]
Epithelial cell adhesion molecule (EPCAM)	OTHBZK5X	EPCAM_HUMAN	Increases Expression	[20]
Splicing factor 45 (RBM17)	OT9ROJCL	SPF45_HUMAN	Decreases Response To Substance	[21]
Equilibrative nucleoside transporter 1 (SLC29A1)	OTLOOZZS	S29A1_HUMAN	Affects Response To Substance	[22]
Nucleophosmin (NPM1)	OTTBYYT0	NPM_HUMAN	Decreases Response To Substance	[23]

References

• [1] ClinicalTrials.gov (NCT00706030) Study Evaluating Neratinib (HKI-272) In Combination With Vinorelbine In Subjects With Solid Tumors And Metastatic Breast Cancer
• [2] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021154)
• [3] Vinorelbine FDA Label
• [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: 7105).
• [5] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [6] Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cyst... Bioorg Med Chem. 2007 Jun 1;15(11):3635-48.
• [7] Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41.
• [8] Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Expert Opin Drug Metab Toxicol. 2016 Aug;12(8):947-57.
• [9] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [10] Irreversible EGFR inhibitor EKB-569 targets low-LET -radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma. PLoS One. 2011;6(12):e29705. doi: 10.1371/journal.pone.0029705. Epub 2011 Dec 29.
• [11] Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem. 2011 Mar 10;54(5):1347-55. doi: 10.1021/jm101396q. Epub 2011 Feb 15.
• [12] Vinca alkaloid and MDR1. Gan To Kagaku Ryoho. 2008 Jul;35(7):1086-9.
• [13] Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8.
• [14] Characterization of human cytochrome P450 isoenzymes involved in the metabolism of vinorelbine. Fundam Clin Pharmacol. 2005 Oct;19(5):545-53.
• [15] Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
• [16] Effects of capecitabine and vinorelbine on cell proliferation, metabolism and COX2 and p16 expression in breast cancer cell lines and solid tumour tissues. Biomed Pharmacother. 2007 Oct;61(9):596-600.
• [17] Identification and Profiling of Environmental Chemicals That Inhibit the TGF/SMAD Signaling Pathway. Chem Res Toxicol. 2019 Dec 16;32(12):2433-2444. doi: 10.1021/acs.chemrestox.9b00228. Epub 2019 Nov 11.
• [18] Acquired protein C deficiency following cisplatinum-navelbine administration for locally advanced breast cancer. Case report. Eur J Gynaecol Oncol. 1999;20(4):323-4.
• [19] Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Br J Cancer. 2006 Jun 5;94(11):1592-8. doi: 10.1038/sj.bjc.6603129.
• [20] Adenocarcinoma cells exposed in vitro to Navelbine or Taxol increase Ep-CAM expression through a novel mechanism. Cancer Immunol Immunother. 2003 Jul;52(7):429-37. doi: 10.1007/s00262-003-0386-7. Epub 2003 Apr 15.
• [21] Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators. Cancer Res. 2005 Aug 1;65(15):6593-600. doi: 10.1158/0008-5472.CAN-03-3675.
• [22] High expression of nucleoside transporter protein hENT1 in Reed-Sternberg cells is associated with treatment failure in relapsed/refractory Hodgkin lymphoma patients treated with gemcitabine, vinorelbine and liposomal doxorubicin - a CALGB 59804 correlative study. Leuk Lymphoma. 2008 Jun;49(6):1202-5. doi: 10.1080/10428190802094237.
• [23] Proteomic identification of differentially expressed proteins associated with the multiple drug resistance in methotrexate-resistant human breast cancer cells. Int J Oncol. 2014 Jul;45(1):448-58.