Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.

细胞周期蛋白依赖性激酶在细胞周期进程中起着重要作用，是癌症治疗的有希望的靶标。但是，由于选择性差，大多数有效的CDK抑制剂缺乏疗效和安全性之间的平衡。考虑到CDK2在肿瘤发生中的作用，选择性抑制CDK2可能会提供针对某些癌症的治疗益处。在这项研究中，设计，合成和评估了一系列的4-苯甲酰氨基-1H-吡唑-3-羧酰胺衍生物。该系列中最具选择性的化合物DC-K2in212对CDK2表现出高效力，并且对A2058黑色素瘤细胞系和MV4-11白血病细胞系具有有效的抗增殖活性，而对人正常细胞系MRC5和LX2的毒性却很低。分子建模表明该化合物DC-K2in212与CDK2的结合模式与C-73（迄今为止报道的最具选择性的CDK2抑制剂）具有相似的结合模式，这可能是针对CDK2的选择性高于CDK1。进一步的生物学研究表明，化合物DC-K2in212抑制CDK2相关的下游信号传导途径，阻断细胞周期进程，并诱导细胞凋亡。因此，化合物DC-K2in212可以作为潜在的CDK2抑制剂用于进一步开发。