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角色。 有丝分裂。许多研究已验证PLK1作为抗肿瘤药物靶点，其抑制作用是 有效抗癌细胞增殖。我们发现了一系列可以结合的化合物 通过一个隐秘的口袋有效地连接到名为 abbapolins 的 PLK1 的 polo-box 结构域，并且 以剂量依赖性方式诱导蛋白酶体介导的 PLK1 蛋白降解 无需添加配体即可募集 E3 连接酶来促进泛素化 (PROTAC 方法）。 abbapolins 还能够抑制 PLK1 特异性标记物的磷酸化 同时有效抑制前列腺癌细胞系的增殖。由于这些令人兴奋的 根据观察结果，我们建议进一步开发这些抑制剂作为有效的 PBD 抑制剂， PLK1 的降解剂，同时使用它们作为化学生物学探针，以提供新的见解 通过构象变化、底物识别和蛋白酶体调节 PLK1 活性 稳定。因此，我们的实验将为细胞中 PLK1 的调节提供新的线索。 水平，同时生成有关分子决定因素和重要特征的新数据 抑制。反过来，这可能有助于了解导致临床缺乏的因素 PLK 有丝分裂激酶 ATP 竞争性抑制剂的活性，同时奠定基础 对于临床前和临床开发，阿巴波林作为癌症治疗剂具有独特的 作用机制。