新型高活性、特异性ATM激酶抑制剂的设计、合成与生物功能研究

The ataxia telangiectasia mutated （ATM） kinase is an atypical serine/threonine protein kinase, playing a central role in maintaining genome integrity by regulating the detection and repair of DNA double-strand breaks. The existing evidences indicate that in the tumor treatment, DDR is one of the resistance mechanisms of radiation therapy and chemotherapy, in which ATM expression and activation connect multiple signaling pathways, regulating the balance of cell proliferation and cell apoptosis. However, few inhibitors of ATM have been reported until now. For the past two years, we previously constructed the homology model of ATM and systematically analyzed the binding mode and key sites of ATM-inhibitors. Furthermore, Compound XD-1 with similar potent compared to the currently known positive compound KU60019 was found by virtual screening. Here, we will focus on designing and developing the ATM-specific inhibitors based on the structure of those lead compounds, combining with combinatorial chemistry strategies and compound optimization strategies including similarity search, binding model analysis and quantitative structure-activity relationship, and further to determine potent, selective ATM inhibitors with novel chemical scaffolds. Totally, 30-50 candidates will be synthesized for evaluation of their biological activity based on enzyme assay, cell assay and drug combination assay. The results will not only provide novel efficient tools for investigating ATM with tumorigenesis, growth and drug resistance research, but also pave a potential path for the development of a novel therapeutic strategy for anti-cancer drugs by targeting ATM.

ATM是一种非典型的丝氨酸/苏氨酸蛋白激酶,通过调节DNA双链断裂的检测和修复在维持基因组完整性中发挥核心作用.研究表明,在肿瘤治疗中DNA损伤应答是放射性疗法和化疗的耐药机制之一,其中ATM的表达和活化连接着多个信号通路,调节着细胞增殖和凋亡的平衡.课题组前期工作首次构建了ATM的结构模型,分析了ATM-抑制剂结合模式和关键作用位点,通过虚拟筛选发现了1个与目前已知阳性参照KU60019活性相当的化合物XD-1.本课题将进一步采用虚拟组合策略设计“靶向集中化合物库”、基于结合模式分析和QSAR在内的优化改造策略,进一步确定2-3类全新化学骨架的ATM抑制剂,合成30-50个高特异性、高活性候选化合物,并进行基于酶水平、细胞水平和联合给药的生物功能评价.本课题将为研究ATM与肿瘤的发生、生长和耐药研究提供高效的工具分子,并为开发以ATM为靶点的抗肿瘤药物奠定基础.

共济失调毛细血管扩张突变（ATM）激酶是一种丝氨酸/苏氨酸蛋白激酶，在DNA双链断裂修复中起关键作用。因此，ATM被认为是放疗和化疗增敏的一个潜在的靶点。在本研究公布工作中，我们通过计算、合成和进一步的生物学评价报告了ATM激动剂A22和抑制剂A41的发现。其中A22在体外表现出较低的细胞毒性，可作为ATM研究的有用工具。此外，我们首次证明ATM抑制剂对MCF-7和SW480细胞具有时间依赖性的增敏作用，在短期治疗中具有拮抗作用，而在长期治疗中具有协同作用，并且ATM激动剂的作用方式与ATM抑制剂相反。进一步的机制研究表明，ATM抑制剂与化疗药物在短期内的拮抗作用是通过抑制p53/p21轴来加速G1/S期细胞周期转变，促进细胞存活。此外，A41在SW480异种移植模型中与化疗药物联合显示出抗肿瘤作用，表明A41是一种很有前途的ATM抑制剂，可增强化疗药物在体内的抗肿瘤作用。综上所述，这些发现将指导ATM抑制剂与化疗药物在进一步的临床前和临床研究中的结合。