HER2/EGFR inhibitor,potent and irreversible
CAS：698387-09-6
分子式：C30H29ClN6O3
分子量：557.04
纯度：98%
存储：Store at -20°C
Background:
IC50: 59 nM (Her-2); 92 nM (EGFR)
HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25–30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Neratinib (HKI-272) is a tyrosine kinase inhibitor under investigation for the treatment breast cancer and other solid tumours.
In vitro: Neratinib (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. Neratinib 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, Neratinib treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation [1].
In vivo: In vivo, Neratinib is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, Neratinib has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers [1].
Clinical trial: Neratinib is in development for the treatment of early- and late-stage HER2-positive breast cancer. Neratanib is being developed by Puma Biotechnology. It will be included in the forthcoming I-SPY2 breast cancer trial (http://en.wikipedia.org/wiki/Neratinib).
Reference:
[1] 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;64(11):3958-65.
