环西洛帕明对Smo蛋白的抑制作用及结构修饰研究

Hedgehog(Hh) signaling is involved in embryonic development and plays an important role in the maintenance of stem cells, tissue repair and regeneration in adult organisms. The erroneous activation of Hh is tightly associated with the occurrence of basal cell carcinoma and medulloblastoma . In addition, several other tumors are co-dependent on hedgehog signaling, examples for this type are cancers of the skin, brain , lung, pancreas, breast.Cyclopamine was the first inhibitor of the Hh pathway to be identified. As a highly selective inhibitor of the transmembrane protein Smoothened (Smo).Unfortunately, its direct development into a drug is hampered by its low metabolic stability (decomposition at pH<3)and poor DMPK (T1/2<2h).In our previous studies, an acid-stable lead compound, Cyclo-cyclopamine (CCP) which an analogue of Cyclopamine was founded. In order to increase potency and selectivity, improve physico-chemical and pharmacokinetic properties, ACD/Percepta Structure Design tools, which can provide predictions for oral bioavailability, CYP450 inhibition, blood brain barrier permeation and many other physiologically relevant properties, was used to design the research compounds.Furthermore, the bioactivity and acid stability of all newly synthesized will be studied. The results will further contribute to their usefulness in biological and medicinal studies.

Hedgehog（Hh）信号通路不仅在胚胎发育和组织器官形成等过程中具有重要作用，而且Hh信号通路在正常人体中的过度激活会导致多种肿瘤及癌症的发生。西洛帕明（Cyclopamine）是最早被证实的一类天然甾体生物碱型Smo蛋白抑制剂，但由于其本身理化性质因素，其成药性较差，如对酸不稳定，半衰期过短。本课题的研究内容是基于本课题组前期发现的一个天然来源、对酸稳定的西洛帕明类似物环西洛帕明（Cyclo-Cyclopamine ，CCP)（专利申请号：201410062394.3），拟以CCP为先导化合物，采用基于理化性质的药物设计与优化方法，对此先导化合物进行结构修饰、活性验证及初步DMPK分析，研究目标是寻找到1-2个安全、有效、可口服的Hh信号通路抑制剂候选药物。

Hedgehog（Hh）信号通路不仅在胚胎发育和组织器官形成等过程中具有重要作用，而且Hh信号通路在正常人体中的过度激活会导致多种肿瘤及癌症的发生。西洛帕明（Cyclopamine）是最早被证实的一类天然甾体生物碱型Smo蛋白抑制剂，但由于其本身理化性质因素，其成药性较差，如对酸不稳定，半衰期过短。本课题的研究内容是基于本课题组前期发现的一个天然来源、对酸稳定的西洛帕明类似物环西洛帕明（Cyclo-Cyclopamine ，CCP)（专利申请号：201410062394.3），拟以CCP为先导化合物，采用基于理化性质的药物设计与优化方法，对此先导化合物进行结构修饰、活性验证及初步DMPK分析，研究目标是寻找到1-2个安全、有效、可口服的Hh信号通路抑制剂候选药物。