设计低毒性的CRM1抑制剂

近几年的研究显示，具有强效广谱抗肿瘤活性的CRM1（出核因子Chromosomal Region Maintenance 1）抑制剂的毒性很可能与其共价结合的方式有关。申请人将根据已知的的结构知识，优化设计全新的非共价结合的CRM1抑制剂，即一种约10个氨基酸的多肽。在两到三轮的蛋白质结晶，结构解析，突变设计和亲和力测定试验后，通过细胞实验评估其抗癌效果及毒性。特效低毒的多肽将被注入白血病小鼠体内做进一步测试。全新设计的非共价结合的CRM1抑制剂，将被用来评估共价结合对毒性的影响，也为将来设计出非共价结合的，更低毒的小分子抗肿瘤药物提供理论基础和模型起点。相关的基础研究，申请者已经以第一作者或者共同第一作者发表在PNAS（2013），Blood（2012）和Leukemia（2013）等期刊上。

Recent research shows that toxicity of potent broad-spectrum anti-cancer CRM1 (nuclear export factor Chromosomal Region Maintenance 1) inhibitors might be related to its covalent binding property. With the knowledge of several CRM1 structures, I plan to design and optimize the first non-covalent CRM1 inhibitor, a 10 amino acids peptide. With two to three rounds of protein crystallization, structure determination, mutation design and binding affinity measurement, peptide’s potency will be accessed by cancer cells, and its toxicity by immortalized cells. Potent and low toxicity candidate will injected to leukemia mouse model to further check its potency and toxicity in vivo. The newly designed peptide will be the first non-covalent CRM1 inhibitor ever known, playing important role in studying influence of covalent binding on toxicity. This study will also provide theoretical foundation for future design of non-covalent, less toxic small molecule anti-cancer drugs and provide a starting template for small molecule design. I have published relevant preliminary research has been published on PNAS (2013), Blood (2012) and Leukemia (2013) as first author or co-first author.