创新药物研发心得及展望  

Drug discovery:our understanding and perspectives

作　　者：陈伟[1] 

机构地区：[1]美国杜克大学医学中心,北卡罗来纳州27710

出　　处：《中国新药杂志》2010年第24期2217-2220,共4页Chinese Journal of New Drugs

摘　　要：文章旨在综述临床前药物研发的思路和过程,并结合笔者实验室的工作探讨如何高效开展药物研发,从而使新药从实验室到病床的转化能更成功顺利完成,且缩短时间。笔者主要针对再生医学(regenerative medicine)和癌症两个治疗领域,重点研究了7次跨膜蛋白细胞受体Smoothened和Frizzled的信号传导和信号通路调节,并以其作为新药靶分子,通过独创的高通量药物筛选平台,获得了许多高效、专一的小分子化合物。由于目前世界上尚无这类急需新药,我们对已经上市的"成熟药物"进行再定向,获得了能用于再生医学的特定糖皮质激素(针对Smoothened)和用于癌症治疗的氯硝柳胺(针对Frizzled)。通过多年努力,系统地建立了一个具有短、中、长期目标的创新药物研发体系。This review will introduce and discuss our laboratory＇s preclinical drug discovery program and lead compound development strategies.Our research focuses on understanding the mechanisms underlying seven-transmembrane receptor signaling;including properties of the Hedgehog/Smoothened and Wnt/Frizzled pathways and their utilization as novel drug targets in regenerative medicine and cancer therapeutics.We have established a state-of-the-art,high throughput,high content drug screening platform that has identified high affinity small molecule lead compounds using screening and structure-activity relationship analysis.In particular,there are no FDA-approved drugs currently targeting the Hedgehog/Smoothened and Wnt/Frizzled signaling pathways.To expedite developing drugs for them,we have screened FDA-approved drug libraries and have re-purposed four glucocorticoids as novel Hedgehog/Smoothened agonists for use in regenerative medicine and niclosamide as a novel Wnt/Frizzled inhibitor for cancer treatment.These candidate molecules are now in preclinical testing with animal disease models.In summary,we have established in our laboratory a unique drug discovery platform to translate basic science discoveries into clinical treatments.

关 键 词：药物研发 靶分子 信号通路 药物筛选 药物再定向 再生医学 癌症 干细胞 

分 类 号：R965.1[医药卫生—药理学]