Development of inhibitors targeting Plk1 polo-box domain

polo样激酶1 （Plk1）是抗癌治疗中最有吸引力的靶点之一。通过靶向Plk1的催化活性来产生Plk1特异性抑制剂的努力已被证明是困难的，因为它与其他结构相关激酶的催化结构域相似。在这里，我们建议开发一类新的单特异性Plk1抑制剂，通过采用一种新的方法来靶向Plk1的非催化性，但功能上必需的PBD。为此，我们与马里兰州贝塞斯达的国家促进转化科学中心（NCATS）合作进行了高通量筛选。我的NIH X01拨款申请已获批准用于该特定项目。从这个筛选中，我们从初级筛选中鉴定了3000个化合物，通过二级培养基通量和三级细胞分析，我们将范围缩小到最后的8个化合物。目前，我们正在通过体外生化试验和细胞试验对这些化合物进行进一步测试，并对这些化合物进行化学修饰以提高其性能。

Polo-like kinase 1 (Plk1) is one of the most attractive targets for anti-cancer therapy. Efforts to generate Plk1-specific inhibitors by targeting the catalytic activity of Plk1 have proven to be difficult due to similarities with the catalytic domains of other structurally related kinases. Here, we propose to develop a new class of mono-specific Plk1 inhibitors by employing a novel approach of targeting the non-catalytic, but functionally essential, PBD of Plk1. To this end, we have carried out a high throughput screen in collaboration with National Center for Advancing Translational Sciences (NCATS), Bethesda, MD. My NIH X01 grant proposal was approved for this particular project. From this screen, we have identified 3,000 compounds from a primary screen, which were narrowed down to the final 8 compounds through secondary medium throughput and tertiary cell-based assays. Currently, we are in the middle of further testing these compounds by using both in vitro biochemical assays and cell-based assays, and carrying out chemical modification of these compounds for improvement.