Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy.
J Med Chem. 2010 Mar 11;53(5):2171-87. doi: 10.1021/jm901710h.
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.
异常增殖是几乎所有癌细胞的一个标志，其是由细胞周期调控机制的破坏介导的。靶向细胞周期蛋白依赖性激酶 (CDK) 和细胞周期蛋白 (Cy) 之间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，可作为现有治疗方法的补充。为了开发三点可变性，对吡唑并[4,3-h]喹唑啉化学类别的扩展进行了研究，得到了一系列能够在体外和体内抑制 CDK 的化合物。从 CDK 选择性但溶解性差的命中化合物 1 开始，我们成功获得了几种对 CDK 和肿瘤细胞显示出增强抑制活性的化合物，并且显示出改善的物理性质和药代动力学行为。我们的研究确定了化合物 59 作为一种高效、口服生物利用的 CDK 抑制剂，在 A2780 卵巢癌异种移植模型中表现出显著的体内疗效。化合物 59 在癌细胞系中的作用机制及其在体内抑制肿瘤生长的能力使其作为潜在的抗肿瘤药物非常有趣。
