Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor
Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor
复制标题
DOI：
10.1158/1535-7163.mct-11-0474
复制
发表时间：
2012-02-01
影响因子：
5.7
通讯作者：
Voliva, Charles F.
中科院分区：
文献类型：
--
作者：
Maira, Sauveur-Michel;Pecchi, Sabina;Voliva, Charles F.
在发现NVP-BEZ235（我们的第一个双泛PI3K/mTOR临床化合物）之后，我们试图从不同化学类别中确定具有不同选择性的磷酸肌醇3激酶（PI3K）抑制剂。实现这些目标的关键是将基于结构的设计方法与在药物化学优化过程中对选定化合物进行深入的药理学评估相结合。在这里，我们报道了2-morpholino嘧啶衍生物pan-PI3K抑制剂NVP-BKM120的生物学特性。该化合物在生化试验中抑制所有四种I类PI3K亚型，对其他蛋白激酶的选择性至少为50倍。该化合物对最常见的体细胞PI3K α突变也有活性，但对相关的III类（Vps34）和IV类（mTOR, DNA-PK） PI3K激酶没有显著抑制作用。与其作用机制一致，NVP-BKM120在机制模型和相关肿瘤细胞系以及下游效应物中以浓度依赖性和途径特异性的方式降低p-Akt的细胞水平。在353个细胞系中测试，NVP-BKM120对携带PIK3CA突变的肿瘤细胞表现出优先抑制作用，与KRAS或PTEN突变模型相反。在机械性异种移植物模型中，通过对p-Akt的显著抑制和对肿瘤生长的抑制，NVP-BKM120显示出剂量依赖性的体内药效学活性。NVP-BKM120在与靶向药物（如MEK或HER2抑制剂）或细胞毒性药物（如多西他赛或替莫唑胺）联合时发挥协同作用。NVP-BKM120的药理学、生物学和临床前安全性支持其临床开发，该化合物正在癌症患者中进行II期临床试验。巨蟹座；11(2), 317 - 28。(c) 2011年aacr。
Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes with a different selectivity profile. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacologic evaluation of selected compounds during the medicinal chemistry optimization process. Here, we report on the biologic characterization of the 2-morpholino pyrimidine derivative pan-PI3K inhibitor NVP-BKM120. This compound inhibits all four class I PI3K isoforms in biochemical assays with at least 50-fold selectivity against other protein kinases. The compound is also active against the most common somatic PI3K alpha mutations but does not significantly inhibit the related class III (Vps34) and class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular levels of p-Akt in mechanistic models and relevant tumor cell lines, as well as downstream effectors in a concentration-dependent and pathway-specific manner. Tested in a panel of 353 cell lines, NVP-BKM120 exhibited preferential inhibition of tumor cells bearing PIK3CA mutations, in contrast to either KRAS or PTEN mutant models. NVP-BKM120 shows dose-dependent in vivo pharmacodynamic activity as measured by significant inhibition of p-Akt and tumor growth inhibition in mechanistic xenograft models. NVP-BKM120 behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide. The pharmacological, biologic, and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is undergoing phase II clinical trials in patients with cancer. Mol Cancer Ther; 11(2);317-28. (C) 2011 AACR.