刺猬通路拮抗剂作为抗肿瘤药物的研发

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.

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。

刺猬通路关键蛋白Smoothened（SMO）拮抗剂Vismodegib于2012年上市，用于治疗基底细胞癌和髓母细胞瘤。然而Vismodegib水溶性差，导致药带动力学呈非线性，加之其毒副作用较强，影响临床用药。本课题组针对Vismodegib的缺点，利用生物电子等排原理，引入SP3杂化碳原子，通过骨架跃迁，得到全新结构的SMO拮抗剂。先导化合物的体外活性及溶解度等理化性质都比Vismodegib有大幅度提高。更重要的是，本课题组的先导化合物在大鼠药代动力学实验中口服给药10， 30， 100mg/kg血药浓度呈线性，生物利用度F%>60%。先导化合物的体外毒理参数良好（CYP IC50>10,000nM, hERG IC50>30,000nM, AMES clean）。在小鼠14天连续给药的毒理实验中（100， 250， 500mg/kg）, 所有动物的行为学，食量消耗等参数都正常，最大耐受量MTD>500mg/kg。 先导化合物在PTCH敲除小鼠皮下成瘤模型中显示了很好的药效。先导化合物能够透过血脑屏障（Brain/Plasma 50%），并在M2脑部原位髓母细胞瘤的模型中有良好的治疗效果。依托本项目资助，课题组共发表本项目标注的SCI论文14篇（其中第一标注论文4篇），申请专利5项（其中授权3项）。