基于药效团叠合策略的乏氧靶向wee1激酶抑制剂的设计、合成及对胰腺癌放疗增敏活性研究

胰腺癌是一种症状隐蔽、恶性程度高且预后极差的肿瘤，其中位生存期仅为6个月左右，诊断后5年生存率不足5%。随着放射治疗在胰腺癌治疗中的比重不断增加，其如何克服其放疗抵抗性已经成为临床上亟待解决关键瓶颈问题。抑制Wee1激酶活性能够提高p53基因缺陷型胰腺癌对放疗的敏感性，但胰腺癌特殊的乏氧微环境导致Wee1抑制剂在病灶部位浓度较低，难以克服其放疗抵抗性。课题组以往研究表明，向小分子药物中引入乏氧靶向基团能够显著提高药物在乏氧环境中的抗肿瘤活性。本项目以adavosertib为先导化合物，采用药效团叠合策略，设计合成乏氧靶向小分子Wee1激酶抑制剂，其作为放疗增敏剂可选择性进入胰腺癌乏氧病灶部位，提高肿瘤细胞对放疗的敏感性。前期研究合成的3个目标化合物能够保持Wee1抑制活性，并表现出放射增敏活性。本研究提供了一条解决胰腺癌放疗抵抗的新途径，同时也为新型肿瘤放射增敏药物的研究奠定理论研究基础。

Pancreatic cancer is refractory with concealed symptoms, high malignancy, and poor prognosis. Its median survival time is only about 6 months, and the 5-year survival rate after diagnosis is less than 5%. With the increasing proportion of radiotherapy in the treatment of pancreatic cancer, how to overcome its radiotherapy resistance has become a key bottleneck in clinic. Inhibition of Wee1 kinase activity can improve the sensitivity of p53 gene-deficient pancreatic cancer to radiotherapy. However, due to the special hypoxic microenvironment of pancreatic cancer, low concentrations of Wee1 inhibitors at focal zones are insufficient to exhibit effective radiosensitivity. Previous researches in our group have shown that introducing hypoxia-targeting groups to drugs can significantly improve the anti-tumor activity in hypoxic environments. In this project, with Adavosertib as the lead compound, hypoxia-targeting small molecular Wee1 kinase inhibitors are designed and synthesized as radiosensitizers through fused pharmacophore strategy, which can improve the radiosensitivity by selectively entering the hypoxic focal zones of pancreatic cancer. Three target compounds synthesized in the previous research could maintain the Wee1 inhibitory activity and show radiosensitizing effect. This research provides a novel way to solve the radiotherapy resistance of pancreatic cancer and lays a theoretical foundation for future tumor radiosensitizers.