Polo-box PLK1 Inhibitors Target Tumors Resistant to ATP Competitive Compounds

Polo-box PLK1 抑制剂靶向对 ATP 竞争性化合物具有抗性的肿瘤

基本信息

批准号：
9347798
负责人：
Campbell McInnes
金额：
$ 22.49万
依托单位：
PPI PHARMACEUTICALS, LLC
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：
2017-05-03 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9347798
关键词：
Active Sites Benzoic Acids Binding Biological Assay Catalytic Domain Cell Line Clinic Clinical Trials Data Development Disadvantaged Drosophila polo protein Drug Evaluation Drug Kinetics Drug Targeting Family Generations Goals In Vitro Laboratories Lead Libraries Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Methods Mitosis Modeling Molecular PLK1 gene PLK3 gene Peptides Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phenotype Phosphotransferases Polo-Box Domain Property Resistance Series Site Specificity Structure-Activity Relationship Therapeutic TimeLine Tumor Suppressor Proteins Work Xenograft procedure analog antitumor agent antitumor drug antitumor effect cancer cell clinical development clinically relevant computer studies design drug development drug discovery in vivo inhibitor/antagonist innovation kinase inhibitor knock-down mutant paralogous gene phase 1 study preclinical development protein protein interaction scaffold subcellular targeting tumor

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. However, recent data suggests that there are two major disadvantages of the conventional approach to blocking the kinase activity of PLK1. First, both general kinome and PLK family specificity is an issue with ATP competitive compounds as they commonly inhibit all paralogs in the Polo-kinase family (including PLK3, a known tumor suppressor). Second, a recent study indicates that a single point mutant in the active site of PLK1 (Cys67Val) results in complete resistance to structurally distinct ATP competitive inhibitors currently in clinical trials, suggesting that the emergence of resistance in the clinic against these agents is a near certainty. Therefore a strategy different from targeting the catalytic domains is urgently needed. PPI Pharmaceuticals will develop PLK1 selective non- ATP competitive inhibitors as effective anti-tumor therapeutics that retain activity against active site mutants resistant to conventional kinase inhibitors. Such compounds will have significant potential for development as anti-tumor agents with decreased likelihood of tumor resistance and off-target effects.

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。但是，最近的数据表明有两个传统方法阻断PLK1的激酶活性的主要缺点。第一的， Kinome和PLK家庭特异性都是ATP竞争化合物的问题它们通常会抑制polo-激酶家族中的所有旁系同源物（包括已知肿瘤PLK3 抑制器）。其次，最近的一项研究表明，在活跃位点中的一个点突变体 PLK1（CYS67VAL）产生对结构上不同ATP竞争性的完全抵抗力目前正在临床试验中的抑制剂，表明临床中的抗药性出现针对这些代理是几乎确定的。因此，一种不同于针对的策略迫切需要催化域。 PPI Pharmaceuticals将开发PLK1选择性非 - ATP竞争性抑制剂作为有效的抗肿瘤疗法，可保留活性活性位点突变体对常规激酶抑制剂具有抗性。这样的化合物将有作为抗肿瘤药物的巨大潜力，肿瘤的可能性降低阻力和脱靶效应。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Peptidomimetic Polo-Box-Targeted Inhibitors that Engage PLK1 in Tumor Cells and Are Selective against the PLK3 Tumor Suppressor.

DOI：
10.1002/cmdc.202000137
发表时间：
2020-06-17
期刊：
ChemMedChem
影响因子：
3.4
作者：
Baxter M;Chapagai D;Craig S;Hurtado C;Varghese J;Nurmemmedov E;Wyatt MD;McInnes C
通讯作者：
McInnes C