特异性CLK1抑制剂的设计合成、构效关系及成药性研究

Recent studies have shown that CLK1 inhibitors can specifically induce autophagy, and are considered as potential therapeutic agents for neurodegenerative diseases, acute liver injury, and so on. However, the activity and specificity of the known CLK1 inhibitors are low, and their side effects are large, which hinder their clinical application. Therefore, discovery of specific CLK1 inhibitors with novel structure and good druggability is strongly demanded. This study will start from four hit compounds, namely L01-L04, discovered in our previous investigation. We shall first dissolve the crystal structures of complexes of CLK1 and these compounds, and then adopt structure-based drug design methods to design new CLK1 inhibitors. The designed compounds will be synthesized by chemical means. In-depth studies including structure optimization and structure-activity relationship (SAR) analysis will be carried out on the synthesized compounds. Next, we shall evaluate the selectivity and preliminary druggability of these compounds, and explore their curative effect in autophagy-related disease animal models. Through the researches of this project, we hope to obtain a number of new CLK1 inhibitors with independent intellectual property rights, high potency and specificity, as well as good druggability. It is expected that this study will lay a solid foundation for the subsequent CLK1-targeting drug research and development.

最近研究发现CLK1抑制剂能特异地诱导细胞自噬，被认为是神经退行性、急性肝损伤等疾病的潜在治疗药物。但目前已报道的CLK1抑制剂的活性和特异性均不高，毒副作用大，阻碍了临床应用。因此，结构新颖、成药性好的CLK1特异性抑制剂的发现是当务之急。本研究以前期发现的4个具有新型骨架结构的苗头化合物（L01-L04）为基础，解析其与CLK1蛋白复合物的晶体结构，采用基于结构的药物分子设计方法，通过化学手段合成新设计的化合物，开展深入的结构优化和构效关系研究。评价小分子的选择性、初步成药性，探索其在自噬相关疾病模型中的治疗效果。以期最终获得具有自主知识产权的新型高活性、特异性并具有良好成药性的CLK1抑制剂，为后续开展靶向CLK1的药物研发打下坚实基础。

Cdc2样激酶1（CLK1）是一种可同时磷酸化底物蛋白的丝/苏氨酸和酪氨酸的双特异性激酶。CLK1与细胞自噬密切相关，被认为是一种重要的自噬相关疾病治疗靶标。然而，目前还特别缺乏高活性和选择性CLK1抑制剂。为此，本项目开展了高活性和选择性CLK1抑制剂的发现研究。通过建立CLK1的表达纯化系统、基于结构的虚拟筛选、结构优化、化学合成、构效关系等研究，获得了多个高活性和选择性CLK1抑制剂。并对其中的一个化合物，即N-(4-methoxybenzyl)-6-(quinolin-6-yl)imidazo[1,2-a]pyridine-3-carboxamide (9e)开展了系统的细胞自噬等相关生物活性评价研究。本项目的研究获得了多个具有自主知识产权的新型高活性、特异性CLK1抑制剂，为后续开展靶向CLK1的药物研发打下坚实基础。