Development of anti-polo-box therapeutic agents

抗polo-box治疗剂的开发

• 批准号: 8763175
• 负责人: Kyung Lee
• 金额: $ 32.48万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763175
• 关键词: Abnormal Cell; Accounting; Applications Grants; Biological Assay; Boxing; Catalytic Domain; Cause of Death; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell division; Cells; Cessation of life; Collaborations; Cultured Cells; Cyclin-Dependent Kinases; Development; Generations; Goals; Human; Laboratories; Malignant Neoplasms; Mission; Mono-S; Normal Cell; Phosphotransferases; Play; Polo-Box Domain; Process; Protein Kinase; Role; Series; Specificity; Testing; Therapeutic Agents; Translational Research; United States National Institutes of Health; addiction; anti-cancer therapeutic; base; cancer cell; cancer therapy; cross reactivity; high throughput screening; human PLK1 protein; inhibitor/antagonist; killings; novel strategies; overexpression; screening; tumorigenesis

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 in cultured cells.

polo样激酶1（PLK1）是抗癌治疗的最有吸引力的靶标之一。由于与其他相关激酶的催化域的相似性，因此很难通过靶向PLK1的催化活性来产生PLK1特异性抑制剂。在这里，我们建议通过采用一种新的靶向非催化性但在功能上必不可少的PLK1的PBD来开发新的单一特异性PLK1抑制剂。为此，我们与国家前进的转化科学中心（NCATS）合作进行了高吞吐量屏幕。我的NIH X01赠款提案已被批准用于该特定项目。从这个屏幕上，我们从主屏幕上鉴定了3,000种化合物，这些化合物通过二级培养基吞吐量和基于第三纪细胞的测定法缩小到最后8种化合物。目前，我们正在进一步测试培养细胞中的这些化合物。