微管蛋白抑制剂（如紫杉醇）广泛用于临床多种恶性肿瘤的治疗，但易产生耐药性。多项研究表明多聚ADP核糖聚合酶-1（PARP-1）的过量表达与微管蛋白抑制剂的肿瘤耐药性密切相关。基于此，我们提出科学设想：微管蛋白和PARP-1双靶点抑制剂可能具有更强的抗肿瘤活性且不易产生耐药（目前国际上尚未有该类抑制剂相关报道）。我们前期采用计算机叠合方法发现了具有双重抑制活性的喹唑啉酮类骨架分子D1；活性测试证实，该化合物对肺鳞癌、黑色素瘤和非小细胞肺癌均显示了良好的抗肿瘤活性，尤其对耐药肿瘤细胞系仍然显示了较好的活性。本项目在前期研究基础上，采用基于受体的活性位点分析、类药性预测、双靶点虚拟筛选等计算机辅助设计方法，进一步优化苗头化合物结构，以提高微管蛋白和PARP-1的选择性和抗肿瘤活性，并进行深入的定性、定量构效关系研究，体内、外抗肿瘤活性及其作用机制研究，为获得双靶向的新型抗肿瘤药物奠定坚实基础。

Tubulin inhibitors (such as paclitaxel) are widely used in clinical treatment for a variety of malignant tumors, but are easy to produce the drug resistance. Multiple studies have demonstrated that overexpression of poly(ADP-ribose) polymerase 1 (PARP-1) is associated closely with cancer drug resistance to tubulin inhibitors. Accordingly, we get the idea that dual inhibitors of tubulin and PARP-1 possibly have better antitumor activity and is less prone to drug resistance (at present there are no such reports). We have discovered a molecule (D1) derived from quinazolinone scaffold by a computer model, which effectively inhibits tubulin and PARP-1. The bioassay of compound D1 certified that it has showed strong antitumor activity against human lung squamous carcinoma, human malignant melanoma, and human non-small cell lung cancer, especially for the drug-resistant cancer cell line. Based on our previous work, we decide to further optimize the lead compound to increase its activity and selectivity, using computer-aided design methods such as active site analysis, drug-likeness prediction and virtual screening. We will also undertake further study on qualitative and quantitative structure-activity relationship, in vitro and in vivo antitumor activity and mechanism. We hope to lay a solid foundation for the development of dual new anticancer drugs.