Development of novel Ku targeted kinase inhibitors

标题：新型Ku靶向激酶抑制剂的开发 -- 摘要： -- DNA-PK，DNA依赖的蛋白激酶，是驱动DNA的癌症治疗的有效靶点 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DNA双链断裂(DSB)的修复，特别是由电离引起的DSB 辐射(IR)。DNA双链断裂的产生是放射治疗临床疗效的机制。 许多破坏DNA的化疗药物被用于治疗癌症。调节负责的途径 修复这些断裂已经被证明对IR或化疗的疗效有深远的影响 诊所。我们已经采取了一种完全独特和新颖的方法来抑制DNA-PK，这是基于我们的 对该激酶如何被激活有广泛的了解，并为当前的 DNA-PK抑制的研究进展。在NHEJ路径中，所有后续步骤的先决条件事件是 Ku70/80杂二聚体与DNA末端的结合，Ku杂二聚体是DNA结合的关键成分 DNA-PK的催化亚基。由于DNA-PKcs需要Ku首先与DSB的DNA末端结合，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的机制来 抑制DNA-PK。我们已经发现和开发了一系列高效和选择性的DNA-PK抑制剂 这是通过破坏Ku与DNA的结合而起作用的。这一系列分子中的先导化合物可以抑制 DNA-PK催化活性在亚微摩尔浓度，在癌细胞中具有单剂抗癌活性 并增强细胞对IR处理的敏感性。我们提出了两个具体目标，以扩展我们的 识别DNA-PK抑制剂并促进这些分子用于抗癌的开发 治疗和提高放疗和化疗的疗效。

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.