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首页> 外文期刊>Molecular cancer therapeutics >Preclinical antitumor activity of the orally available heat shock protein 90 inhibitor NVP-BEP800.
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Preclinical antitumor activity of the orally available heat shock protein 90 inhibitor NVP-BEP800.

机译：口服热休克蛋白90抑制剂NVP-BEP800的临床前抗肿瘤活性。

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摘要

Heat shock protein 90 (Hsp90) is a ubiquitously expressed molecular chaperone with ATPase activity involved in the conformational maturation and stability of key signaling molecules involved in cell proliferation, survival, and transformation. Through its ability to modulate multiple pathways involved in oncogenesis, Hsp90 has generated considerable interest as a therapeutic target. NVP-BEP800 is a novel, fully synthetic, orally bioavailable inhibitor that binds to the NH(2)-terminal ATP-binding pocket of Hsp90. NVP-BEP800 showed activity against a panel of human tumor cell lines and primary human xenografts in vitro at nanomolar concentrations. In A375 melanoma and BT-474 breast cancer cell lines, NVP-BEP800 induced client protein degradation (including ErbB2, B-Raf(V600E), Raf-1, and Akt) and Hsp70 induction. Oral administration of NVP-BEP800 was well tolerated and induced robust antitumor responses in tumor xenograft models, including regression in the BT-474 breast cancer model. In these tumor models, NVP-BEP800 modulated Hsp90 client proteins and downstream signaling pathways at doses causing antitumor activity. NVP-BEP800 showed in vivo activity in a variety of dosing regimens covering daily to weekly schedules, potentially providing a high degree of flexibility in dose and schedule within the clinical setting. Overall, given the mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, NVP-BEP800 is an exciting new oral Hsp90 inhibitor warranting further development. Mol Cancer Ther; 9(4); 906-19. (c)2010 AACR.
机译：热休克蛋白90（Hsp90）是一种普遍表达的分子伴侣，具有ATPase活性，参与细胞增殖，存活和转化的关键信号分子的构象成熟和稳定性。通过其调节涉及肿瘤发生的多种途径的能力，Hsp90已经引起了作为治疗靶标的极大兴趣。 NVP-BEP800是一种新颖的，完全合成的，口服生物利用的抑制剂，可与Hsp90的NH（2）-末端ATP结合袋结合。 NVP-BEP800在纳摩尔浓度下对一组人类肿瘤细胞系和原代人类异种移植物表现出活性。在A375黑色素瘤和BT-474乳腺癌细胞系中，NVP-BEP800诱导客体蛋白降解（包括ErbB2，B-Raf（V600E），Raf-1和Akt）和Hsp70诱导。在肿瘤异种移植模型中，包括在BT-474乳腺癌模型中的回归，口服NVP-BEP800具有良好的耐受性，并诱导了强大的抗肿瘤反应。在这些肿瘤模型中，NVP-BEP800以引起抗肿瘤活性的剂量调节Hsp90客户蛋白和下游信号通路。 NVP-BEP800在多种给药方案中均表现出体内活性，这些给药方案涵盖了每天至每周的时间表，从而可能在临床环境中在剂量和时间表方面提供高度的灵活性。总体而言，考虑到作用机理，临床前活性概况，耐受性和药物特性，NVP-BEP800是令人兴奋的新型口服Hsp90抑制剂，有待进一步开发。分子癌疗法; 9（4）; 906-19。 （c）2010年美国机管学会（AACR）。

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