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（PLK 1）是调节进入和进展的核心参与者， 分裂。许多研究已经证实PLK 1是一个抗肿瘤药物靶点，其抑制作用是通过抑制PLK 1的表达来实现的。 对癌细胞有很强的抗增殖作用。我们发现了一系列化合物 通过一个神秘的口袋，有效地连接到PLK 1的polo-box结构域，称为abbapolins， 以剂量依赖性方式诱导蛋白酶体介导的PLK 1蛋白降解 不添加配体以募集E3连接酶来促进泛素化（PROTAC 方法）。阿巴布林还能够抑制PLK 1特异性标志物的磷酸化 同时有效地抑制前列腺癌细胞系的增殖。由于这些令人兴奋的 观察，我们建议进一步开发这些抑制剂作为有效的PBD抑制剂， PLK 1的降解剂，同时将它们用作化学生物学探针， 通过构象变化、底物识别和蛋白酶体调节PLK 1活性 稳定因此，我们的实验将为PLK 1在细胞内的调节提供新的线索。 水平，同时产生新的数据的分子决定因素和功能的重要 抑制作用反过来，这可以提供对导致缺乏临床治疗的因素的理解。 活性的ATP竞争性抑制剂的PLK有丝分裂激酶，同时奠定基础 对于临床前和临床开发，abbapolins作为癌症治疗剂具有独特的 作用机制。