p53磷酸化位点S15和S392在非小细胞肺癌重构p53功能的作用及萘甲酰亚胺类化合物的干预机制研究

p53失活是非小细胞肺癌发病和治疗无效的常见诱因，使得重构p53功能作为非小细胞肺癌治疗方式成为可能。但是研究发现，目前基于抑制p53-MDM2相互作用的激活策略不能有效的重构p53抗癌功能，其原因是p53功能不能被完全激活所致。本课题提出明确p53在激活状态的关键分子构象，并基于此分子构象筛选得到能够持续、稳定维持此分子构象的p53激活剂可能是研究真正有效药物的关键。本课题拟在非小细胞肺癌遗传背景下通过定点突变、正向激活、反向抑制等手段研究p53磷酸化位点S15和S392在非小细胞肺癌重构p53功能的作用及萘甲酰亚胺类化合物NA-17的干预机制，找到p53功能依赖型分子构象，明确NA-17在p53蛋白的结合位点，为新型靶向治疗药物的研发提供参考。

p53 inactivation the common cause of morbidity and treatment-nonresponsive in Non–Small-Cell Lung Cancer make it possible for therapeutic strategy based on p53 restoration. However, activation strategy based on interrupting p53-MDM2 interaction can not effectively restore p53 anticancer function because of the not fully activated p53 function. We suggest that to clarify the key molecule conformation of activated p53 and to obtain the p53 activator which could be sustained to maintain the key molecular conformation may be the root cause for developing effective drug. It is therefore important to study the roles of phosphoserine 15 and 392 in restoring p53 function and intervention mechanisms of naphthalimide compound NA-17 by point mutation, positive activation and reverse inhibition. After this project is completed, the p53 function dependent molecular conformation and the binding site of NA-17 in p53 protein will be supplied, which could provide a theoretical basis for new drug design.