Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors.
Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors.
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DOI：
10.1021/jm901710h
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发表时间：
2010-02
影响因子：
7.3
通讯作者：
G. Traquandi;M. Ciomei;D. Ballinari;E. Casale;N. Colombo;V. Croci;F. Fiorentini;A. Isacchi;A. L
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文献类型：
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作者：
G. Traquandi;M. Ciomei;D. Ballinari;E. Casale;N. Colombo;V. Croci;F. Fiorentini;A. Isacchi;A. L
通过破坏保持细胞周期受控的机制介导的异常增殖是几乎所有癌细胞的标志。靶向细胞周期蛋白依赖性激酶（CDKs）和细胞周期蛋白（Cy）之间的复合物并抑制其活性的化合物被认为是有前途的抗肿瘤药物，以补充现有的治疗。进行了吡唑并[4，3-h]喹唑啉化学类别的扩展，以开发三个可变点，从而产生一系列能够在体外和体内抑制CDK的化合物。从CDK选择性但难溶的命中化合物1开始，我们成功地获得了几种化合物，其显示出对CDK和肿瘤细胞的增强的抑制活性，并显示出改善的物理性质和药代动力学行为。我们的研究鉴定出化合物59是一种高效的、口服生物可利用的CDK抑制剂，其在A2780卵巢癌异种移植模型上表现出显著的体内功效。化合物59对癌细胞系的作用机制及其在体内抑制肿瘤生长的能力使该化合物作为潜在的抑制剂非常令人感兴趣。
Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under control is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDKs) and cyclins (Cy) and inhibiting their activity are regarded as promising antitumor agents to complement the existing therapies. An expansion of pyrazolo[4,3-h]quinazoline chemical class oriented to the development of three points of variability was undertaken leading to a series of compounds able to inhibit CDKs both in vitro and in vivo. Starting from the CDK selective but poorly soluble hit compound 1, we succeeded in obtaining several compounds showing enhanced inhibitory activity both on CDKs and on tumor cells and displaying improved physical properties and pharmacokinetic behavior. Our study led to the identification of compound 59 as a highly potent, orally bioavailable CDK inhibitor that exhibited significant in vivo efficacy on the A2780 ovarian carcinoma xenograft model. The demonstrated mechanisms of action of compound 59 on cancer cell lines and its ability to inhibit tumor growth in vivo render this compound very interesting as potential antineoplastic agent.