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Novel Chemical Biology Probes based on Selective Inhibitors of the Polo-Box Domain of PLK1

基于 PLK1 Polo-Box 结构域选择性抑制剂的新型化学生物学探针

基本信息

批准号：
9517781
负责人：
Campbell McInnes
金额：
$ 7.16万
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：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9517781
关键词：
Active Sites Affinity Aftercare Anaphase Antimitotic Agents Antineoplastic Agents Binding Biology Catalytic Domain Cell Cycle Cell Line Cell model Cells Chemicals Clinic Clinical Clinical Trials Data Development Drug Targeting Family Family member Foundations Generations Goals Investigation Laboratories Lead Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Methods Mitosis Mitotic Modeling Molecular PLK1 gene PLK3 gene PTEN gene Peptides Permeability Pharmaceutical Preparations Phenotype Phosphopeptides Phosphorylation Phosphotransferases Polo-Box Domain Prodrugs Reporting Resistance Resistance development Role Site Specificity Structure-Activity Relationship Substrate Interaction Suggestion TP53 gene Therapeutic Tumor Suppressor Proteins Validation antitumor agent antitumor drug antitumor effect base clinically relevant drug discovery high throughput screening inhibitor/antagonist innovation knock-down lead optimization mutant neoplastic cell next generation novel novel therapeutics pressure protein protein interaction recruit small molecule success tumor

项目摘要

The Polo-box domain (PBD) is critical for mitotic functions of PLK1 and has shown to be required for substrate recruitment and sub-cellular localization. The McInnes laboratory has made significant progress toward the development of PLK1 selective inhibitors based on PBD inhibition that have minimal activity on the PLK3 tumor suppressor and which retain activity against PLK1 site mutants that are resistant to clinically utilized ATP competitive inhibitors. These compounds will be high value chemical biology probes for further establishing the phenotypic consequences of inhibiting PLK1 in a non-ATP competitive fashion through the PBD, in validating the PBD as an anti-mitotic drug target and in their potential as next generation therapeutics. This proposal is significant and innovative with respect to the following: 1) An innovative strategy called REPLACE has been developed to generate cell cycle specific CDK inhibitors as anti-tumor therapeutics. Furthermore the McInnes laboratory validated this strategy for the PLK1 PBD revealing that fragment ligated peptidic inhibitors discovered though REPLACE have respectable anti-proliferative activity and phenotypes consistent with target inhibition. 2) Chemical biology probes that target the PBD will be highly selective for PLK1 and possess minimal affinity for the PLK3 tumor suppressor. This is important to further establish the phenotypic consequences of blocking the PLK1 PBD selectively and also to avoid deleterious effects of PLK3 inhibition in the development of anti-tumor therapeutics. We have already demonstrated that our most potent PLK1 PBD domain inhibitors have minimal activity against PLK3. 3) PBD targeted compounds will retain antitumor activity against tumor cells that have acquired resistance to ATP-based inhibitors. As described above, a single point mutant (C67V) is capable of rendering PLK1 resistant to structurally diverse ATP-based inhibitors. Targeting non-catalytic functions of PLK1 should result in less selective pressure for resistance and PBD inhibitors might be used in combination with ATP-based inhibitors as a synergistic means of PLK1 targeting in the clinic. 4) Current lead compounds induce a phenotype in treated cells that recapitulates a PLK1 knockdown. This stands in contrast to weakly binding small molecule PBD inhibitors reported that only induced partial effects, and may not possess a desirable level of anti-tumor activity. Some of our observed phenotypes are novel and suggestive of anaphase catastrophe, known to promote tumor selectivity. 5) Novel PBD inhibitors will be tumor selective compounds. Recent discoveries that PLK1 inhibition is synthetically lethal in PTEN deficient, mutant Ras and p53 deficient cancers will be exploited to generate tumor selective compounds. Non-peptidic inhibitors will be used in cellular studies to confirm tumor cell specificity, PLK1 selectivity, and cellular phenotypes consistent with on target inhibition.

Polo-box 结构域 (PBD) 对于 PLK1 有丝分裂功能至关重要，并且已被证明是底物所必需的募集和亚细胞定位。麦金尼斯实验室在这方面取得了重大进展开发基于 PBD 抑制的 PLK1 选择性抑制剂，对 PLK3 肿瘤具有最小的活性抑制子，并保留针对对临床使用的 ATP 具有抗性的 PLK1 位点突变体的活性竞争性抑制剂。这些化合物将成为高价值的化学生物学探针，用于进一步建立通过 PBD 以非 ATP 竞争方式抑制 PLK1 的表型后果，验证 PBD 作为抗有丝分裂药物靶点及其作为下一代疗法的潜力。这个提议是在以下方面具有重大意义和创新性： 1) 开发了一种名为 REPLACE 的创新策略来生成细胞周期特异性 CDK 抑制剂作为抗肿瘤治疗剂。此外，麦金尼斯实验室验证了这一策略 PLK1 PBD揭示了虽然REPLACE发现的片段连接肽抑制剂令人尊敬的抗增殖活性和与靶标抑制一致的表型。 2）针对PBD的化学生物学探针将对PLK1具有高度选择性并具有对 PLK3 肿瘤抑制因子的亲和力极小。这对于进一步确定表型非常重要选择性阻断 PLK1 PBD 的后果以及避免 PLK3 的有害影响抑制抗肿瘤疗法的发展。我们已经证明，我们最有效的 PLK1 PBD 结构域抑制剂对 PLK3 的活性极小。 3) PBD靶向化合物将保留针对已经获得的肿瘤细胞的抗肿瘤活性对 ATP 抑制剂的耐药性。如上所述，单点突变体（C67V）能够使 PLK1 对结构多样的基于 ATP 的抑制剂具有抗性。针对非催化功能 PLK1 应导致耐药性的选择压力较小，PBD 抑制剂可用于与基于 ATP 的抑制剂联合作为临床上 PLK1 靶向的协同手段。 4) 目前的先导化合物在处理的细胞中诱导出再现 PLK1 的表型击倒。这与弱结合小分子 PBD 抑制剂形成鲜明对比，据报道，仅诱导部分效应，并且可能不具有理想水平的抗肿瘤活性。我们观察到的一些表型是新颖的，提示后期灾难，已知可促进肿瘤选择性。 5）新型PBD抑制剂将是肿瘤选择性化合物。最近发现 PLK1 抑制作用 PTEN 缺陷、突变 Ras 和 p53 缺陷癌症中的合成致死将被用来产生肿瘤选择性化合物。非肽抑制剂将用于细胞研究以确认肿瘤细胞特异性、PLK1 选择性和细胞表型与靶点抑制一致。