靶向WNT信号通路的豪猪蛋白抑制剂抗肿瘤药物的研发

The Wnt signaling pathway is a pivotal developmental pathway. It operates through control of cellular functions such as proliferation, differentiation, migration and polarity. Aberrant Wnt signaling has been implicated in the formation and metastasis of tumors. Porcupine is a component of the Wnt signaling pathway. It is a member of the membrane-bound O-acyltransferase family of proteins. Porcupine catalyzes the palmitoylation of Wnt proteins, a process which is required for their secretion and activity. LGK974, the most advanced porcupine inhibitor developed by Novartis, had been progressed to clinical testing in 2012. LGK974 and most other porcupine inhibitors all feature an amide bond which is essential to their pharmacological activities. However, the amide functionality often leads to fast clearance and poor bioavailability. We had successfully applied a scaffold-hopping strategy to replace the amide functionality with heterocycles and obtained more potent porcupine inhibitors than LGK974 with improved physical-chemical properties and bioavailability. We will design and synthesize porcupine/tankyrase dual inhibitors and Wnt/Hedgehog dual inhibitors to address potential resistance which is common in cancer treatment. Our goal is to develop best in class, brand new Wnt pathway inhibitors as novel anticancer therapy

控制转移与复发是治疗恶性肿瘤的难题，即使是最先进的靶向药物对其疗效也不显著。基于此，Wnt信号通路的研究受到科学界高度重视，这是因为Wnt通路在乳腺癌、结肠癌等多种恶性肿瘤的发生发展过程中异常活化，更因为Wnt通路是胚胎发育通路，调控肿瘤干细胞、控制肿瘤微环境,对肿瘤转移与复发起举足轻重的作用。胚胎通路（Wnt/Hedgehog等）已成为目前肿瘤研究的热点。本项目以Wnt信号通路关键蛋白豪猪蛋白（Porcupine）为靶标，参考LGK974（第一个进入临床的豪猪蛋白抑制剂）的结构，运用生物电子等排和骨架迁越的设计理念，成功除去了这类分子中普遍存在的酰胺键药效基团，获得了全新结构，活性和药代动力学参数等都更优化的化合物，并拟设计合成Porcupine/Tankyrase双靶点拮抗剂和Wnt/Hedgehog双通路拮抗剂，用以解决潜在的耐药性，为开发出优秀的Wnt通路拮抗剂打下坚实基础

Wnt信号通路的研究受到科学界高度重视。Wnt通路不仅在乳腺癌、结肠癌等多种恶 性肿瘤的发生发展过程中异常活化，而且是胚胎发育通路，调控肿瘤干细胞、控制 肿瘤微环境,对肿瘤转移与复发起举足轻重的作用。胚胎通路（Wnt/Hedgehog等）已成为目前 肿瘤研究的热点。本项目以Wnt信号通路关键蛋白豪猪蛋白（Porcupine）为靶标，参考LGK974 （第一个进入临床的豪猪蛋白抑制剂）的结构，运用生物电子等排和骨架迁越的设计理念，成功除去了这类分子中普遍存在的酰胺键药效基团，获得了全新结构的化合物。基于全新结构的优选化合物对porcupine蛋白抑制达0.08nM，是LGK974的五倍，其他理化参数、成药性良好。大鼠和狗中的药代动力学参数显示，优选化合物的暴露量（AUC>4000nM.h/mg）和生物利用度（>60%）良好。优选化合物在Wnt驱动的肿模型中抑瘤效果显著。亚长毒7天小鼠实验证明，优选化合物无明显毒性。依托本项目资助，课题组共发表本项目标注的SCI论文16篇（其中第一标注论文4篇），申请专利2项，培养博士生2名、硕士生6名。