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

• 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
• 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

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.

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。然而，最近的数据表明，有两个 阻断 PLK1 激酶活性的传统方法的主要缺点。第一的， 一般激酶组和 PLK 家族特异性都是 ATP 竞争性化合物的一个问题，因为 它们通常抑制 Polo 激酶家族中的所有旁系同源物（包括 PLK3，一种已知的肿瘤 抑制器）。其次，最近的一项研究表明，活性位点的单点突变 PLK1 (Cys67Val) 导致对结构不同的 ATP 竞争性的完全抵抗 抑制剂目前正在进行临床试验，提示临床中出现了耐药性 对抗这些代理几乎是肯定的。因此，采取不同于瞄准目标的策略 迫切需要催化结构域。 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，可保留抗肿瘤活性 对传统激酶抑制剂具有抗性的活性位点突变体。此类化合物将具有 具有降低肿瘤发生可能性的抗肿瘤药物的巨大开发潜力 阻力和脱靶效应。

项目成果

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