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Neratinib

Neratinib 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. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

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.

 Current developer:   Wyeth Inc.

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2: Belani CP. The role of irreversible EGFR inhibitors in the treatment of non-small cell lung cancer: overcoming resistance to reversible EGFR inhibitors. Cancer Invest. 2010 May;28(4):413-23. Review. PubMed PMID: 20307200.

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4: Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, Awada A, Ranade A, Jiao S, Schwartz G, Abbas R, Powell C, Turnbull K, Vermette J, Zacharchuk C, Badwe R. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010 Mar 10;28(8):1301-7. Epub 2010 Feb 8. PubMed PMID: 20142587.

5: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Dec;31(10):661-700. PubMed PMID: 20140276.

6: Yamashita T, Iwata K. [New development in the treatment of breast cancer. II. Future anti-HER2 therapy]. Gan To Kagaku Ryoho. 2009 Dec;36(13):2551-4. Japanese. PubMed PMID: 20104676.

7: Bose P, Ozer H. Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer. Expert Opin Investig Drugs. 2009 Nov;18(11):1735-51. Review. PubMed PMID: 19780706.

8: Morris PG, Hudis CA. Personalizing therapy for metastatic breast cancer. Expert Rev Anticancer Ther. 2009 Sep;9(9):1223-6. PubMed PMID: 19761426.

9: Ocaña A, Amir E. Irreversible pan-ErbB tyrosine kinase inhibitors and breast cancer: current status and future directions. Cancer Treat Rev. 2009 Dec;35(8):685-91. Epub 2009 Sep 4. Review. PubMed PMID: 19733440.

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11: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Apr;31(3):183-226. PubMed PMID: 19536362.

12: Ito Y, Kobayashi K. [Chemotherapy for breast cancer refractory to anthracycline, taxane or trastuzumab]. Gan To Kagaku Ryoho. 2009 May;36(5):726-9. Japanese. PubMed PMID: 19461171.

13: Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Jänne PA, Eder JP, Naughton MJ, Ellis MJ, Jones SF, Mekhail T, Zacharchuk C, Vermette J, Abbas R, Quinn S, Powell C, Burris HA. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res. 2009 Apr 1;15(7):2552-8. Epub 2009 Mar 24. PubMed PMID: 19318484.

14: Leone JP, Dudek AZ. Enzyme replacement therapy for Gaucher's disease in patient treated for non-small cell lung cancer. Anticancer Res. 2008 Nov-Dec;28(6B):3937-9. PubMed PMID: 19192653.

15: Riely GJ. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. J Thorac Oncol. 2008 Jun;3(6 Suppl 2):S146-9. Review. PubMed PMID: 18520300.

16: Wissner A, Mansour TS. The development of HKI-272 and related compounds for the treatment of cancer. Arch Pharm (Weinheim). 2008 Aug;341(8):465-77. Review. PubMed PMID: 18493974.

17: Godin-Heymann N, Ulkus L, Brannigan BW, McDermott U, Lamb J, Maheswaran S, Settleman J, Haber DA. The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol Cancer Ther. 2008 Apr;7(4):874-9. PubMed PMID: 18413800.

18: Wong KK. HKI-272 in non small cell lung cancer. Clin Cancer Res. 2007 Aug 1;13(15 Pt 2):s4593-6. Review. PubMed PMID: 17671147.

19: Li D, Shimamura T, Ji H, Chen L, Haringsma HJ, McNamara K, Liang MC, Perera SA, Zaghlul S, Borgman CL, Kubo S, Takahashi M, Sun Y, Chirieac LR, Padera RF, Lindeman NI, Jänne PA, Thomas RK, Meyerson ML, Eck MJ, Engelman JA, Shapiro GI, Wong KK. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell. 2007 Jul;12(1):81-93. PubMed PMID: 17613438.

20: Toffoli G, De Mattia E, Cecchin E, Biason P, Masier S, Corona G. Pharmacology of epidermal growth factor inhibitors. Int J Biol Markers. 2007 Jan-Mar;22(1 Suppl 4):S24-39. Review. PubMed PMID: 17520578.

21: Yuza Y, Glatt KA, Jiang J, Greulich H, Minami Y, Woo MS, Shimamura T, Shapiro G, Lee JC, Ji H, Feng W, Chen TH, Yanagisawa H, Wong KK, Meyerson M. Allele-dependent variation in the relative cellular potency of distinct EGFR inhibitors. Cancer Biol Ther. 2007 May;6(5):661-7. Epub 2007 Feb 13. PubMed PMID: 17495523.

22: Sequist LV. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Oncologist. 2007 Mar;12(3):325-30. Review. PubMed PMID: 17405897.

23: Minami Y, Shimamura T, Shah K, LaFramboise T, Glatt KA, Liniker E, Borgman CL, Haringsma HJ, Feng W, Weir BA, Lowell AM, Lee JC, Wolf J, Shapiro GI, Wong KK, Meyerson M, Thomas RK. The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272. Oncogene. 2007 Jul 26;26(34):5023-7. Epub 2007 Feb 19. PubMed PMID: 17311002.

24: Shimamura T, Ji H, Minami Y, Thomas RK, Lowell AM, Shah K, Greulich H, Glatt KA, Meyerson M, Shapiro GI, Wong KK. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res. 2006 Jul 1;66(13):6487-91. PubMed PMID: 16818618.

25: Arteaga CL. EGF receptor mutations in lung cancer: from humans to mice and maybe back to humans. Cancer Cell. 2006 Jun;9(6):421-3. Review. PubMed PMID: 16766261.

26: Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, Mahmood U, Mitchell A, Sun Y, Al-Hashem R, Chirieac LR, Padera R, Bronson RT, Kim W, Jänne PA, Shapiro GI, Tenen D, Johnson BE, Weissleder R, Sharpless NE, Wong KK. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell. 2006 Jun;9(6):485-95. Epub 2006 May 25. PubMed PMID: 16730237.

27: Ji H, Zhao X, Yuza Y, Shimamura T, Li D, Protopopov A, Jung BL, McNamara K, Xia H, Glatt KA, Thomas RK, Sasaki H, Horner JW, Eck M, Mitchell A, Sun Y, Al-Hashem R, Bronson RT, Rabindran SK, Discafani CM, Maher E, Shapiro GI, Meyerson M, Wong KK. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7817-22. Epub 2006 May 3. PubMed PMID: 16672372; PubMed Central PMCID: PMC1456806.

28: Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7665-70. Epub 2005 May 16. PubMed PMID: 15897464; PubMed Central PMCID: PMC1129023.

29: Tsou HR, Overbeek-Klumpers EG, Hallett WA, Reich MF, Floyd MB, Johnson BD, Michalak RS, Nilakantan R, Discafani C, Golas J, Rabindran SK, Shen R, Shi X, Wang YF, Upeslacis J, Wissner A. Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem. 2005 Feb 24;48(4):1107-31. PubMed PMID: 15715478.

30: Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004 Jun 1;64(11):3958-65. PubMed PMID: 15173008.