Development of non-ATP competitive chemical biology probes to elucidate mechanisms of PLK1 activation and stability.

开发非 ATP 竞争性化学生物学探针以阐明 PLK1 激活和稳定性的机制。

• 批准号: 10290769
• 负责人: Campbell McInnes
• 金额: $ 20.9万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10290769
• 关键词: Affinity; Allosteric Regulation; Binding; Binding Sites; Biology; Biophysics; Cell Cycle; Cells; Chemicals; Clinical; Data; Development; Dimerization; Dose; Drug Targeting; Hydrophobicity; Ligand Binding; Ligands; Light; Malignant Neoplasms; Measures; Mediating; Mitosis; Mitotic; Molecular; Molecular Conformation; Names; PLK1 gene; Pharmaceutical Chemistry; Phosphorylation; Phosphothreonine; Phosphotransferases; Play; Polo-Box Domain; Proteins; Regulation; Role; Series; Site; Structure; Sumoylation Pathway; TPT1 gene; Tail; Therapeutic; Time; Ubiquitination; Work; antitumor drug; base; cancer cell; cell growth regulation; clinical development; design; dimer; event cycle; experimental study; improved; inhibitor/antagonist; inorganic phosphate; insight; monomer; multicatalytic endopeptidase complex; novel; polo-like kinase kinase 1; preclinical development; prevent; prostate cancer cell line; recruit; tumor; ubiquitin-protein ligase

Polo-like kinase 1 (PLK1) is a central player in regulating entry into and progression through mitosis. Many studies have validated PLK1 as an anti-tumor drug target, and its inhibition is potently anti-proliferative to cancer cells. We have discovered a series of compounds that bind potently to the polo-box domain of PLK1 named abbapolins through a cryptic pocket and which induce proteasome mediated degradation of the PLK1 protein in a dose dependent manner without the addition of a ligand to recruit an E3 ligase to promote ubiquitination (PROTAC approach). The abbapolins are also able to inhibit the phosphorylation of a PLK1 specific marker while potently inhibiting the proliferation of prostate cancer cell lines. As a result of these exciting observations, we propose to further develop these inhibitors as potent PBD inhibitors and degraders of PLK1 while using them as chemical biology probes to provide new insights the regulation of PLK1 activity through conformational change, substrate recognition and proteasomal stability. Our experiments will therefore shed new light into the regulation of PLK1 at the cellular level while generating novel data on the molecular determinants and features important for inhibition. In turn this may provide understanding of the factors contributing to the lack of clinical activity for the ATP competitive inhibitors of the PLK mitotic kinases while laying the groundwork for preclinical and clinical development the abbapolins as cancer therapeutics with a unique mechanism of action.

polo样激酶1 （PLK1）是调节进入和进展的核心参与者