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。

基本信息

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
项目类别：
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

项目摘要

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.

类似马球的激酶1（PLK1）是调节进入和进步的核心参与者有丝分裂。许多研究已将PLK1验证为抗肿瘤药物靶标，其抑制作用是对癌细胞有效抗增殖。我们发现了一系列结合的化合物通过一个神秘的口袋，有力地到达PLK1的Polo-Box域名，名为Abbapolins，并且以剂量依赖性的方式诱导PLK1蛋白的蛋白酶体介导的降解没有添加配体来募集E3连接酶以促进泛素化（Protac）方法）。 Abbapolins还能够抑制PLK1特异性标记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结果观察结果，我们建议将这些抑制剂进一步发展为有效的PBD抑制剂和 PLK1的降级器使用它们作为化学生物学探针提供新见解通过构象变化，底物识别和蛋白酶体调节PLK1活性稳定。因此，我们的实验将把新的光放在细胞处的PLK1调节中同时生成有关分子决定因素的新数据，并且特征对于抑制。反过来，这可能会理解导致缺乏临床的因素 PLK有丝分裂激酶的ATP竞争抑制剂的活性为了临床前和临床开发，Abbapolins作为癌症治疗药作用机理。