Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase
Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase
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DOI：
10.1158/0008-5472.can-03-2868
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发表时间：
2004-06-01
期刊：
影响因子：
11.2
通讯作者：
Wissner, A
中科院分区：
文献类型：
--
作者：
Rabindran, SK;Discafani, CM;Wissner, A
HER-2属于受体酪氨酸激酶ErbB家族，与多种癌症有关。在25-30%的乳腺癌患者中发现HER-2过表达，这预示着原发疾病患者预后较差。曲妥珠单抗（赫赛汀）是一种HER-2单克隆抗体，被专门批准用于HER-2阳性乳腺癌，但仅对这些肿瘤的一部分有效。因此，通过小分子激酶抑制剂阻断HER-2的功能，是抑制HER-2阳性肿瘤生长的一种有吸引力的替代策略。HKI-272是一种有效的HER-2抑制剂，在体外对HER-2过表达的人乳腺癌细胞系具有高度活性。它还抑制表皮生长因子受体（EGFR）激酶和EGFR依赖性细胞的增殖。在与细胞增殖抑制一致的剂量下，HKI-272降低HER-2受体在细胞中的自磷酸化，并作为一种不可逆的结合抑制剂发挥作用，最有可能是通过靶向受体atp结合口袋中的半胱氨酸残基。与预测的HER-2失活效应一致，HKI-272处理细胞导致下游信号转导事件和细胞周期调节途径的抑制。这导致阻滞在细胞分裂周期的G(1)-S （Gap 1/DNA合成）阶段，最终导致细胞增殖下降。在体内，当每日口服一次时，HKI-272在HER-2和egfr依赖的肿瘤异种移植模型中有活性。基于其良好的临床前药理特征，ki -272已被选为乳腺癌和其他her -2依赖性癌症抗肿瘤药物的候选药物。
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. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. 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. This leads to arrest at the G(1)-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 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, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers.