Highly specific ATR inhibitors for the targeted treatment of a broad spectrum of cancers

项目总结 针对共济失调毛细血管扩张症和RAD3相关激酶(ATR)的特异性靶向是一种新兴的 治疗多种癌症的战略，尤其是那些目前缺乏有效治疗的癌症。 抑制ATR选择性地杀死受到致癌压力的细胞，交替延长端粒 (ALT)或失去双链断裂(DSB)修复机制(ATM、BRCA1或BRCA2缺乏)。的确， 消除这类癌症的ATR抑制水平对正常组织的毒性最小 增殖控制，包括对传统化疗药物最敏感的药物，如 骨髓和肠道。因此，ATR抑制剂为癌症提供了一种新的有效的治疗方法，一 这比传统化疗引起的副作用更少。 Atrin制药公司合成了一系列新的小分子，在低纳摩尔范围内抑制ATR 在培养细胞中的浓度。这些化合物具有已知的最高的抑制ATR和 在体内对同一家族的其他激酶(ATM、DNA-PKcs和 MTOR)，它们基本上不被所有先前报道的ATR抑制剂靶向。在此，我们建议 通过以下方式完成我们对Atrin的ATR抑制剂系列的初步评估：1)进一步定义 作用和增强ATRN系列的药理特性，以及2)探索 ATRN系列与传统疗法相结合杀死癌症。这项提议的最终目标是 研究目的是生产一种可应用于临床的独特的特异性ATR小分子抑制剂。

PROJECT SUMMARY Specific targeting of the Ataxia Telangiectasia and Rad3-related kinase (ATR) represents an emerging strategy to treat a broad spectrum of cancers, most notably those that currently lack effective treatments. Suppression of ATR selectively kills cells subjected to oncogenic stress, alternative lengthening of telomeres (ALT) or loss of double strand break (DSB) repair mechanisms (ATM, BRCA1, or BRCA2 deficiency). Indeed, levels of ATR suppression that eliminate such cancers do so with minimal toxicity to tissues under normal proliferative control, including those that are the most sensitive to traditional chemotherapeutics such as the bone marrow and intestine. Therefore, ATR inhibitors provide a new and effective treatment for cancer, one that causes fewer side effects than conventional chemotherapies. Atrin Pharmaceuticals has synthesized a novel series of small molecules that inhibit ATR at low nanomolar concentrations in cultured cells. These compounds have the highest known potency for inhibiting ATR and maintain >833-fold lower in vivo activity towards other kinases of the same family (ATM, DNA-PKcs and mTOR), which are substantially off-targeted by all previously reported ATR inhibitors. Herein, we propose to complete our preliminary evaluation of Atrin’s ATR inhibitor series by: 1) further defining the mechanism of action and enhancing the pharmacologic properties of the ATRN series, and 2) exploring the ability of the ATRN series to kill cancers in combination with conventional therapies. The ultimate goal of this proposed research is to produce a uniquely specific small-molecule inhibitor of ATR that can be applied in the clinic.