针对小细胞肺癌的高选择性ATR激酶抑制剂的发现研究

小细胞肺癌是肺癌中一种恶性程度高、增殖快、侵袭性强的癌症，目前临床上仍然缺乏有针对性的靶向治疗药物。有研究表明，在小细胞肺癌中由于高度的复制压力及化疗药物的使用会激活ATR信号通路，从而使ATR激酶成为潜在治疗小细胞肺癌的药物靶点。然而，由于ATR所在的PIKK家族中激酶的高同源性，发展高选择性的ATR激酶抑制剂具有挑战性。在前期的研究中，结合药物重定位与高通量筛选的策略，我们初步发展了在PIKK家族中取得一定选择性苗头化合物IHMT-98，但是其活性以及选择性等性质还有待进一步改进。本项目拟以现有苗头化合物结构为基础，通过对PIKK家族蛋白的空间结构及结合模式分析，使用骨架跃迁及药效片段组合的药物化学策略进行进一步结构优化，从而发展高选择性高活性的ATR激酶抑制剂，以此为工具，探索ATR抑制剂对小细胞肺癌体内外作用效果，阐明其作用机制，为发展新型小细胞肺癌的靶向药物提供前瞻性理论支持。

Because of the rapid proliferation and high invasiveness, small cell lung cancer (SCLC) is the most malignant type of lung cancer, chemotherapy is the first-line therapy. However, almost all patients develop drug resistance within one year, development of small-molecule targeted drugs is favored. The high degree of replication pressure and DNA damage after chemotherapy make the DNA damage response (DDR) pathway highly activated in small cell lung cancer cells, ATR kinase is a potential target for the treatment of small cell lung cancer and ATR inhibitor can overcome the drug resistance and side-effect of chemotherapy due to its overexpression and the core of DDR in SCLC. However, due to the high homology of kinases in the PIKK family, it is still challenge to obtain selective ATR inhibitors. Based on the structure of IHMT-98, using the structure hoppings and fragment hybride strategies, through the analysis of binding mode and structure differences among PIKK family members, we aim to develop highly selective and potent ATR inhibitor, elucidate its therapeutic effect against small cell lung cancer as single or combination of chemotherapy and pave the way for ATR drug discovery.