Biphenyl-4-carboxylic acid-[2-(1H-indol-3-yl)-ethyl]-methylamide 1 (CA224) is a nonplanar analogue of fascaplysin (2) that specifically inhibits Cdk4–cyclin D1 in vitro. Compound 1 blocks the growth of cancer cells at G₀/G₁ phase of the cell cycle. It also blocks the cell cycle at G₂/M phase, which is explained by the fact that it inhibits tubulin polymerization. Additionally, it acts as an enhancer of depolymerization for taxol-stabilized tubulin. Western blot analyses of p53-positive cancer cells treated with compound 1 indicated upregulation of p53, p21, and p27 proteins together with downregulation of cyclin B1 and Cdk1. Compound 1 selectively induces apoptosis of SV40 large T-antigen transformed cells and significantly reduces colony formation efficiency, in a dose-dependent manner, of lung cancer cells. It is efficacious at 1/10th of the MTD against human tumors derived from HCT-116 and NCI-H460 cells in SCID mouse models. The promising efficacy of compound 1 in human xenograft models as well as its excellent therapeutic window indicates its potential for clinical development.

中文翻译：

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联苯-4-羧酸[2-（1 H-吲哚-3-基）-乙基]-甲基酰胺（CA224），法拉第新的非平面类似物，抑制Cdk4和微管蛋白聚合：体外和体内抗癌活性的评估

联苯-4-羧酸-[2-（1 H-吲哚-3-基）-乙基]-甲基酰胺1（CA224）是fascaplysin的非平面类似物（2），在体外特异性抑制Cdk4-cyclin D1。化合物1在细胞周期的G ₀ / G ₁期阻止癌细胞的生长。它还阻止了G ₂ / M期的细胞周期，这是因为它抑制了微管蛋白的聚合。此外，它还可以作为紫杉醇稳定的微管蛋白的解聚促进剂。用化合物1处理的p53阳性癌细胞的蛋白质印迹分析表示p53，p21和p27蛋白的上调以及细胞周期蛋白B1和Cdk1的下调。化合物1选择性地诱导SV40大T抗原转化的细胞凋亡，并以剂量​​依赖性方式显着降低肺癌细胞的集落形成效率。在SCID小鼠模型中，它对来自HCT-116和NCI-H460细胞的人类肿瘤的MTD的效力是其的1/10。化合物1在人异种移植模型中的有希望的功效及其出色的治疗窗口表明了其在临床开发中的潜力。