Development of inhibitors targeting Plk1 polo-box domain

Polo-like kinase 1（Plk 1）是目前最具吸引力的抗癌靶点之一。通过靶向Plk 1的催化活性来产生Plk 1特异性抑制剂的努力已被证明是困难的，这是由于与其他结构相关激酶的催化结构域的相似性。在这里，我们建议开发一类新的单特异性Plk 1抑制剂，采用一种新的方法，针对非催化，但功能上必不可少的，PBD的Plk 1。为此，我们与马里兰州贝塞斯达的国家推进转化科学中心（NCATS）合作进行了高通量筛选。我的NIH X 01资助提案被批准用于这个特定的项目。从这个筛选中，我们已经从初级筛选中鉴定了3，000种化合物，通过二级培养基通量和三级基于细胞的测定将其缩小到最终的8种化合物。目前，我们正在通过使用体外生化测定和基于细胞的测定来进一步测试这些化合物，并对这些化合物进行化学修饰以进行改进。

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.