新型KRAS-PDEδ抑制剂的设计、合成和抗胰腺癌活性研究

KRAS-PDEδ protein-protein interaction has attracted great attention for its application in anti-pancreatic cancer treatment in recent years. However, there are many problems remained to be resolved such as constrained structure type and poor druggable properties of its inhibitors. Based on the theory and previous research, we adopted fragment-based drug design strategy and found that the IDO1 inhibitor in clinical study is an effective inhibitor targeting KRAS-PDEδ protein-protein interaction for the first time. Then, a series of novel small-molecule inhibitors by modifications of the IDO1 inhibitor were designed and synthesized. Fortunately, the preliminary structure-activity relationship and biological activity studies indicated that compound 10 showed the greatest inhibitory activity both in molecular and cellular levels and appropriate pharmacological properties, verifying the feasibility of the study preliminarily. On this basis, we intend to focus on the mechanism of compound 10, verification of druggability of KRAS-PDEδ protein-protein interaction, and further improvement of KRAS-PDEδ inhibitors via structural optimization. The project is supposed to discover promising KRAS-PDEδ inhibitors with novel structures, laying a solid foundation for the development of innovative drugs against pancreatic cancer.

KRAS-PDEδ蛋白-蛋白相互作用是近年来抗胰腺癌药物治疗的热门靶点，但其抑制剂存在结构类型有限、成药性差等缺陷。结合理论及研究基础，本课题采用基于片段的药物设计策略，首次发现已进入临床研究的IDO1药物是有效的PDEδ抑制剂，并设计合成了新型KRAS-PDEδ小分子抑制剂。经初步构效关系及生物活性研究，证实先导化合物10在分子、细胞水平均具有优秀的活性及成药性，初步验证了科学假说的可行性。在此基础上，本项目拟对先导化合物10重点开展阐明作用机制，验证靶点成药性，通过结构优化进一步提升KRAS-PDEδ抑制剂的成药性及抗胰腺癌活性等方面的研究。目标是获得具有成药前景的新型KRAS-PDEδ抑制剂，为开发抗胰腺癌创新药物奠定基础。

KRAS-PDEδ蛋白-蛋白相互作用是当下肿瘤领域在研药物的热门靶点。本项目围绕阻断KRAS-PDEδ相互作用，重点开展了以下两方面研究。1、新型PDEδ蛋白降解靶向嵌合体的研究。首次提出运用蛋白靶向嵌合体技术，设计合成得到靶向PDEδ的PROTAC分子21个。其中大部分化合物具有良好的体外活性，以化合物B6的降解活性最佳（DC50 = 3.6 μM），其蛋白结合活性（KD = 9.0 nM），对SW480的IC50值为8 μM。在小鼠结肠癌SW480移植瘤模型中，化合物B6体内抑瘤率达43%，均明显优于阳性药deltazinone。2、新型KRAS-PDEδ螺环小分子抑制剂的研究。采用基于结构的药物设计进行结构优化，设计合成得到蛋白结合活性提高、体外抗肿瘤活性增强、理化性质改善的螺环KRAS-PDEδ小分子抑制剂20个。其中高活性化合物36I，在胰腺癌PDX小鼠模型中，抑瘤率为57.3%，是已报道中体内药效最佳的KRAS-PDEδ小分子抑制剂。进一步机制实验验证，以上两类新型KRAS-PDEδ小分子抑制剂均能有效阻断KRAS-PDEδ蛋白-蛋白相互作用，干扰了KRAS在细胞膜上的定位，下调KRAS下游通路关键蛋白Akt的磷酸化水平，促使KRAS突变的肿瘤细胞系的凋亡。本研究丰富了KRAS-PDEδ抑制剂的结构类型，为KRAS-PDEδ相互作用的药物研发提供了新的策略。在本项目资助下，共发表标注SCI论文2篇，Journal of Medicinal Chemistry（IF = 8.039），1篇发表于药学学报英文版，Acta Pharmaceutica Sinica. B（IF = 14.903）；共计培养博士研究生1名，硕士研究生1名。