基于天然产物的新型蛋白酶体抑制剂的先导发现与优化

Proteasome plays a very important role in catalyzing protein degradation through the ubiquitin-proteasome pathway，and regulates degradation of tumor growth associated protein. These years, proteasome has emerged a new therapeutic target for antitumor drugs. The proteasome inhibitors bortezomib and carfilzomib have been approved by FDA, and are currently used in clinic for treating multiple myeloma. The current inhibitors that have entered human clinical trials are still lack, and exist several problems, including side-effects and poor pharmacokinetics property. Therefore, the discovery of new proteasome inhibitors is the key issue. Natural products have served as a rich reservoir for therapeutic drugs and bioactive leads. As previous study of structure simplification for TMC-95A template,an integrated approach to discover novel anticancer proteasome inhibitor leads based on natural products is proposed herein, composed of molecular modeling, virtual screening, molecular design and synthesis and biological evaluation. Chemoinformatic techniques are used to extract the information of structural features and properties from natural products, then a virtual focused library is generated by collecting chemical data for virtual screening. Considering requirements of both synthetic feasibility and structural diversity, preferred target molecules are selected for chemical synthesis and further evaluated for inhibition on proteasomes and effects on tumor growth . The evidence-based feedback from screening-design-synthesis-evaluation- structure-activity relationship helps the project to obtain high activity, low toxicity, and novel structure proteasome inhibitors, and offer new chemical entities for anti-cancer therapy.

蛋白酶体是泛素－蛋白酶体的蛋白质降解通路中的关键催化蛋白，对肿瘤生长相关蛋白的降解起重要调控作用，近年来成为抗肿瘤药物治疗的新靶点。已成功上市的蛋白酶体抑制剂有bortezomib和carfilzomib，用于治疗多发性骨髓瘤。目前进入临床研究的抑制剂数量尚少且大多存在毒副作用大、药代动力学性质不理想等问题。因此开发新型蛋白酶体抑制剂是关键。天然产物在新药创制中起到重要作用。本项目拟在前期TMC-95A模板简化研究基础上，综合运用分子模拟、虚拟筛选、设计合成及生物评价等方法进一步拓展基于天然产物的新先导发现。利用化学信息学手段提取天然产物的结构和性质信息，建立定向库进行虚拟筛选，兼顾合成可行性和结构多样性要求，优选目标分子合成并评价其对蛋白酶和肿瘤细胞生长的抑制作用。根据筛选-设计-合成-评价-构效关系的循证反馈，以期获得高活性低毒结构新颖的蛋白酶体抑制剂，为抗肿瘤治疗提供新的化学实体。

Bortezomib和Carfilzomib是目前被美国FDA批准上市的蛋白酶体抑制药物，主要用于治疗多发性骨髓瘤。蛋白酶体成为抗肿瘤的药物研发的新靶点。本项目采用多种分子模拟的设计方法，基于天然产物的药效团和骨架迁越合成了两个结构类型的46个化合物，并评价了目标化合物的分子水平和细胞水平的抑制活性以及肿瘤细胞生长抑制作用的生物学活性。.本项目共获得26个对人类20S蛋白酶体的抑制浓度（IC50）在10-6M水平以上的新型抑制剂，初步总结了构效关系；并对20S蛋白酶体三个活性位点（CT-L,T-L和C-L）的抑制作用分别进行生物学评价，初步分析了对CT-L位点的选择性抑制作用。此外，对分子水平活性较好的的几个化合物进行细胞水平活性测试，有两个化合物表现出抑制活性。本项目的研究，为蛋白酶体抑制剂的研发提供了新的先导结构。.基于此项目的研究结果，已申请中国发明专利一项，发表期刊论文2篇，会议论文2篇，培养硕士研究生两名。