刺猬通路拮抗剂作为抗肿瘤药物的研发

项目名称： 刺猬通路拮抗剂作为抗肿瘤药物的研发

项目编号： No.81473090

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张小虎

作者单位： 苏州大学

项目金额： 80万元

中文摘要： 转移与复发是恶性肿瘤的特点，也是治疗恶性肿瘤的难题，即使是最先进的靶向药物对肿瘤的转移与复发疗效也不显著。近来，hedgehog（Hh）信号通路（刺猬通路）的研究受到了科学界越来越多的重视，这不仅是因为Hh通路异常活化在许多包括基底细胞癌、髓母细胞瘤等肿瘤的发生发展过程起了举足轻重的作用，更重要的是，Hh通路是胚胎发育通路，对调控肿瘤干细胞、控制肿瘤微环境,从而对控制肿瘤转移与复发有重要作用。其他胚胎通路成员包括Wnt和Notch，胚胎通路的研究已成为最近几年肿瘤研究的热点之一。本项目针对目前唯一获得FDA批准的刺猬通路拮抗剂Vismodegib的理化性质和活性较差，已产生耐药性等问题，运用骨架迁越的设计理念，成功获得全新结构，活性和理化性质都更优化的化合物，并拟采用异构拮抗，共价结合等科学手段，解决Vismodegib的耐药性，为开发出最优的第二代刺猬通路拮抗剂打下坚实基础。

中文关键词： 构效关系；抗肿瘤；药物设计；计算机辅助药物设计；药物合成

英文摘要： The hedgehog (Hh) signaling pathway is a critical developmental pathway which regulates patterning, growth and cell migration during embryonic development. However, its role in adulthood is substantially curtailed to tissue maintenance and repair. Under normal conditions, the endogenous ligands sonic hedgehog, Indian hedgehog and desert hedgehog bind to their cellular membrane receptor Patched (Ptch), relieving the repression effect of Ptch on GPCR-like receptor Smoothened (Smo). Smo activation triggers a series of intracellular events ultimately lead to specific gene expression mediated by the Gli family transcription factors. Aberrant Hh signaling has been linked to numerous human cancers. Mutational inactivation of the inhibitory pathway component such as Ptch (lost function of Ptch) or activation of Smo (gain function of Smo) leads to constitutive ligand-independent activation of the Hh signaling pathway, resulting in cancers such as basal cell carcinoma and medulloblastoma. Ligand-dependent activation of Hh signaling is involved in lung, colorectal, prostate, pancreatic, breast and some blood cancers. Thus, inhibition of the aberrant Hh signaling represents a promising approach for novel anticancer therapy. Cyclopamine, a naturally occurring alkaloid, was the first Hh signaling pathway inhibitor to be reported in the literature, and it was later identified as a Smo antagonist. A number of synthetic Smo antagonists had been reported in recent years. The most advanced in the class, GDC-0449 (Vismodegib), was approved by FDA in January 2012 for patients with locally advanced or metastatic basal cell carcinoma which was not suitable for operation. This approval highlighted the first embryonic pathway inhibitor for the treatment of human cancer. However, Vismodegib suffered from moderate potency and poor physical-chemical properties [high melting point (264 C) and poor solubility (9.5 μg/mL)], more importantly, there were reports that patient developed resistance to Vismodegib via SMO mutations. In order to solve these problems, we had successfully applied a scaffold-hopping strategy to obtain more potent hedgehog inhibitors than Vismodegib with improved physical-chemical properties. We will utilize allosteric and irreversible medicinal chemistry strategies to design and synthesize hedgehog antagonists to address the drug resistance which Vismodegib had acquired. Our goal is to develop best in class, brand new hedgehog antagonists as novel anticancer therapy.

英文关键词： hedgehog;smoothened;antagonist;GPCR;oncology