Abstract：
Cyclin-dependent kinase 2 (CDK2) is a member of CDK family of kinases (CDKs) that regulate the cell cycle. Its inopportune or over-activation leads to uncontrolled cell cycle progression and drives numerous types of cancers, especially ovarian, uterine, gastric cancer, as well as those associated with amplified CCNE1 gene. However, developing selective lead compound as CDK2 inhibitors remains challenging owing to similarities in the ATP pockets among different CDKs. Herein, we described the optimization of compound 1, a novel macrocyclic inhibitor targeting CDK2/5/7/9, aiming to discover more selective and metabolically stable lead compound as CDK2 inhibitor. Molecular dynamic (MD) simulations were performed for compound 1 and 9 to gain insights into the improved selectivity against CDK5. Further optimization efforts led to compound 22, exhibiting excellent CDK2 inhibitory activity, good selectivity over other CDKs and potent cellular effects. Based on these characterizations, we propose that compound 22 holds great promise as a potential lead candidate for drug development.
摘要：
细胞周期蛋白依赖性激酶2（CDK2）是调节细胞周期的CDK激酶（CDK）家族的成员。它的不合时宜或过度激活导致不受控制的细胞周期进展，并驱动多种类型的癌症，尤其是卵巢,子宫,胃癌,以及与扩增的CCNE1基因相关的基因。然而,开发选择性先导化合物作为CDK2抑制剂仍然具有挑战性，因为不同CDK之间的ATP口袋相似。在这里，我们描述了化合物1的优化，一种靶向CDK2/5/7/9的新型大环抑制剂，旨在发现更多选择性和代谢稳定的先导化合物作为CDK2抑制剂。对化合物1和9进行分子动力学(MD)模拟以获得对CDK5的改进选择性的见解。进一步的优化努力导致化合物22，表现出优异的CDK2抑制活性，对其他CDK具有良好的选择性和有效的细胞效应。基于这些特征，我们认为化合物22有望成为药物开发的潜在候选药物.
