肠癌是我国常见的恶性肿瘤，预后差，亟需有效的药物。以MDM2/p53为靶点是潜在的肿瘤治疗策略。APG-115是本团队自主研发的第二代MDM2-p53小分子抑制剂。文献报道9%的肠癌细胞存在MDM2过表达，我们的前期研究发现APG-115对p53野生型肠癌细胞有效，APG-115在体外能增加p53野生型肠癌细胞p21和PUMA的表达，诱导凋亡。同时LC3-I随着药物浓度的增加逐渐向LC3-II转化，提示APG-115可能诱导肠癌细胞内自噬。自噬在APG-115抑制肠癌细胞生长中起着怎样的作用？APG-115作用后自噬和凋亡之间的关系如何尚未见报道。我们将进一步探索APG-115单药和联合化疗在体内能否抑制肠癌的增殖，并揭示其作用机制，重点阐述自噬的作用。该研究的开展不仅为以MDM2/p53为靶点开发新型靶向抗肿瘤药物打下基础，也为晚期肠癌患者的治疗提供新的思路，进而改善晚期肠癌患者的预后。

Colorectal cancer is a common malignant tumor in China with poor prognosis. MDM2/p53 is a potential therapeutic target for cancer therapy. APG-115 is the second generation of MDM2-P53 small molecule inhibitor developed by our team. It was reported that MDM2 was overexpressed in 9% colon cancer cells. Our preliminary study found that APG-115 showed potent cell growth inhibitory activity in vitro with low nanomolar potencies in colon cancer cell lines containing wild-type p53. Mechanistically, APG-115 increased PUMA and p21 expression, activated p53 - mediated apoptosis in tumor cells retaining wild-type p53. Meanwhile, we found that APG-115 decreased BCL2 and increased LC3-II expression which indicated that APG-115 might induce autophagy in colon cancer cells. .What is the role of autophagy in APG-115 inhibition of colon cancer cell growth? What is the interaction between autophagy and apoptosis? Our present study will further explore whether APG-115 single agent or combining with chemotherapy can inhibit the growth of colon cancer in vivo. We will also explore the mechanism. The fulfilling of APG-115 can not only lay a foundation to develop MDM2/p53 as a potential therapeutic target for cancer therapy, but also provide new ideas for the treatment of patients with advanced colorectal cancer and finally improve the prognosis of patients with advanced colorectal cancer.