A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.

合成了一系列新的细胞周期蛋白依赖性激酶（CDKs）抑制剂，它们在细胞周期控制和细胞转录调控中起着关键作用。对酶和细胞分析的系统研究导致鉴定出具有针对CDK4和CDK9的纳摩尔效价和针对一组肿瘤细胞系的有效抗增殖活性的化合物X22。X22可以诱导癌细胞系中的细胞周期停滞和细胞凋亡。X22剂量依赖性地抑制癌细胞CDK下游的信号通路。体内抗肿瘤活性测定，口服X22在小鼠模型中导致明显的肿瘤消退而没有明显的毒性。优越的抗癌功效的体外和体内的X22证明联合细胞周期和转录CDK的耗尽都促成了抗肿瘤活性。两者合计，同时抑制细胞周期和转录CDK活性为进一步的结构优化提供了宝贵的指导。