Development of novel Ku targeted kinase inhibitors

新型 Ku 靶向激酶抑制剂的开发

• 批准号: 9409232
• 负责人: Katherine Pawelczak
• 金额: $ 30万
• 依托单位: NERX BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409232
• 关键词: Active Sites; Advanced Development; Adverse effects; Antineoplastic Agents; Binding; Cancer cell line; Catalytic Domain; Cell Death; Cell Line; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Trials; Complex; DNA; DNA Binding; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA-PKcs; DNA-dependent protein kinase; Data; Development; Dose; Drug Sensitization; Drug usage; Event; G22P1 gene; Generations; Health; Human; Ionizing radiation; Knowledge; Lead; Left; Malignant Neoplasms; Measures; Modality; Modeling; Molecular; Nonhomologous DNA End Joining; Normal tissue morphology; Outcome; Pathway interactions; Phase; Phosphotransferases; Play; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Recruitment Activity; Research; Role; Safety; Series; Specificity; Therapeutic; Therapeutic Effect; Toxic effect; Treatment Efficacy; anti-cancer therapeutic; base; cancer cell; cancer therapy; chemotherapy; clinical efficacy; experimental study; inhibitor/antagonist; kinase inhibitor; mimetics; novel; novel strategies; radiosensitizing; repaired; response; tissue culture; tumor

Title: Development of novel Ku targeted kinase inhibitors    Abstract    DNA-PK, the DNA-dependent protein kinase, is a validated target for cancer therapeutics that drives the DNA damage response and plays a critical role in the non-homologous end joining (NHEJ) DNA repair pathway. NHEJ is responsible for the repair of DNA double strand breaks (DSB), particularly those induced by ionizing radiation (IR). The generation of DNA DSBs is the mechanism of clinical efficacy of radiation therapy and numerous DNA damaging chemotherapeutic drugs used to treat cancer. Modulating the pathway responsible for repairing these breaks has been shown to have a profound impact on the efficacy of IR or chemotherapy in the clinic. We have taken a completely unique and novel approach to inhibiting DNA-PK that is based on our extensive knowledge about how the kinase is activated and affords considerable advantages to current approaches in DNA-PK inhibition. In the NHEJ pathway, the prerequisite event for all subsequent steps is the binding of the Ku70/80 heterodimer to DNA ends, and the Ku heterodimer is the key DNA-binding component of the catalytic subunit of DNA-PK. As DNA-PKcs requires Ku to first bind the DNA terminus of the DSB, which then recruits and activates the kinase, we have targeted this Ku-DNA interaction as a novel mechanism to inhibit DNA-PK. We have discovered and developed a series of highly potent and selective DNA-PK inhibitors that act via disrupting the binding of Ku to DNA. The lead compound from this series of molecules inhibits DNA-PK catalytic activity at sub-micromolar concentrations, has single-agent anti-cancer activity in cancer cell lines, and potentiates cellular sensitivity to IR treatment. We propose two specific aims that expand upon our identified DNA-PK inhibitors and advance the development of these molecules for use as anti-cancer therapeutics and to increase the efficacy of radiation and chemotherapy.

标题：新型 Ku 靶向激酶抑制剂的开发    抽象的    DNA-PK 是一种 DNA 依赖性蛋白激酶，是驱动 DNA 的癌症治疗的经过验证的靶点 损伤反应并在非同源末端连接 (NHEJ) DNA 修复途径中发挥关键作用。 NHEJ 负责修复 DNA 双链断裂 (DSB)，特别是电离引起的断裂 辐射（IR）。 DNA DSB的产生是放射治疗和临床疗效的机制 许多用于治疗癌症的 DNA 损伤化疗药物。调节负责的途径 修复这些断裂已被证明对 IR 或化疗的疗效产生深远影响 诊所。我们采取了一种完全独特且新颖的方法来抑制 DNA-PK，该方法基于我们的 关于激酶如何激活的广泛知识，为当前的激酶提供了相当大的优势 DNA-PK 抑制的方法。在 NHEJ 途径中，所有后续步骤的先决事件是 Ku70/80异二聚体与DNA末端的结合，Ku异二聚体是关键的DNA结合成分 DNA-PK 的催化亚基。由于DNA-PKcs需要Ku首先结合DSB的DNA末端，这 然后招募并激活激酶，我们将这种 Ku-DNA 相互作用作为一种新机制 抑制DNA-PK。我们发现并开发了一系列高效、选择性的 DNA-PK 抑制剂 通过破坏 Ku 与 DNA 的结合来发挥作用。这一系列分子的先导化合物抑制 亚微摩尔浓度的 DNA-PK 催化活性，在癌细胞中具有单药抗癌活性 线，并增强细胞对红外线治疗的敏感性。我们提出了两个具体目标，以扩展我们的 鉴定出 DNA-PK 抑制剂并推进这些分子用于抗癌的开发 治疗并提高放疗和化疗的疗效。