Neratinib
CAS#: 698387-09-6
Description: Neratinib, also known as HKI-272 or PB272, is an orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity. Neratinib binds to the HER-2 receptor irreversibly, thereby reducing autophosphorylation in cells, apparently by targeting a cysteine residue in the ATP-binding pocket of the receptor. Treatment of cells with this agent results in inhibition of downstream signal transduction events and cell cycle regulatory pathways; arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle; and ultimately decreased cellular proliferation. Neratinib also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells.
Synonym: HKI272; HKI 272; HKI-272; PB272; PB 272; PB-272; Neratinib.
IUPAC/Chemical Name: (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
THEORETICAL ANALYSIS
Name: Neratinib
CAS#: 698387-09-6
Chemical Formula: C30H29ClN6O3
Exact Mass: 556.19897
Molecular Weight: 557.04
Elemental Analysis: C, 64.68; H, 5.25; Cl, 6.36; N, 15.09; O, 8.62
TECHNICAL DATA
ADDITIONAL INFORMATION
HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways.
REFERENCES
1: Saura C, Garcia-Saenz JA, Xu B, Harb W, Moroose R, Pluard T, Cortés J, Kiger C, Germa C, Wang K, Martin M, Baselga J, Kim SB. Safety and Efficacy of Neratinib in Combination With Capecitabine in Patients With Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. J Clin Oncol. 2014 Oct 6. pii: JCO.2014.56.3809. [Epub ahead of print] PubMed PMID: 25287822.
2: Schwab CL, English DP, Roque DM, Bellone S, Lopez S, Cocco E, Nicoletti R, Rutherford TJ, Schwartz PE, Santin AD. Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo. Gynecol Oncol. 2014 Oct;135(1):142-8. doi: 10.1016/j.ygyno.2014.08.006. Epub 2014 Aug 12. PubMed PMID: 25124161.
3: Neratinib Graduates to I-SPY 3. Cancer Discov. 2014 Jun;4(6):624. doi: 10.1158/2159-8290.CD-NB2014-055. Epub 2014 Apr 7. PubMed PMID: 24891343.
4: Zhang X, Munster PN. New protein kinase inhibitors in breast cancer: afatinib and neratinib. Expert Opin Pharmacother. 2014 Jun;15(9):1277-88. doi: 10.1517/14656566.2014.913570. Epub 2014 Apr 30. PubMed PMID: 24787047.
5: Gandhi L, Bahleda R, Tolaney SM, Kwak EL, Cleary JM, Pandya SS, Hollebecque A, Abbas R, Ananthakrishnan R, Berkenblit A, Krygowski M, Liang Y, Turnbull KW, Shapiro GI, Soria JC. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol. 2014 Jan 10;32(2):68-75. doi: 10.1200/JCO.2012.47.2787. Epub 2013 Dec 9. PubMed PMID: 24323026.
6: Jankowitz RC, Abraham J, Tan AR, Limentani SA, Tierno MB, Adamson LM, Buyse M, Wolmark N, Jacobs SA. Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2 positive breast cancer: an NSABP Foundation Research Program phase I study. Cancer Chemother Pharmacol. 2013 Dec;72(6):1205-12. PubMed PMID: 24077916.
7: Canonici A, Gijsen M, Mullooly M, Bennett R, Bouguern N, Pedersen K, O’Brien NA, Roxanis I, Li JL, Bridge E, Finn R, Siamon D, McGowan P, Duffy MJ, O’Donovan N, Crown J, Kong A. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer. Oncotarget. 2013 Oct;4(10):1592-605. PubMed PMID: 24009064; PubMed Central PMCID: PMC3858548.
8: Martin M, Bonneterre J, Geyer CE Jr, Ito Y, Ro J, Lang I, Kim SB, Germa C, Vermette J, Wang K, Wang K, Awada A. A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer. Eur J Cancer. 2013 Dec;49(18):3763-72. doi: 10.1016/j.ejca.2013.07.142. Epub 2013 Aug 15. PubMed PMID: 23953056.
9: Chow LW, Xu B, Gupta S, Freyman A, Zhao Y, Abbas R, Vo Van ML, Bondarenko I. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Br J Cancer. 2013 May 28;108(10):1985-93. doi: 10.1038/bjc.2013.178. Epub 2013 Apr 30. PubMed PMID: 23632474; PubMed Central PMCID: PMC3670493.
10: Awada A, Dirix L, Manso Sanchez L, Xu B, Luu T, Diéras V, Hershman DL, Agrapart V, Ananthakrishnan R, Staroslawska E. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Ann Oncol. 2013 Jan;24(1):109-16. doi: 10.1093/annonc/mds284. Epub 2012 Sep 11. PubMed PMID: 22967996.
