基于分子片段的药物设计:热休克蛋白90抑制剂的发现与开发研究进展

Fragment-based drug design:discovery and development of HSP90 inhibitor

分子伴侣热休克蛋白90(HSP90)在肿瘤细胞中处于活化状态,呈现高表达,在维持肿瘤细胞生存、增殖、侵袭、转移,以及血管增生过程中具有关键作用,作用于HSP90 N端ATP结合域的天然产物格尔德霉素及其衍生物在体内对多种肿瘤具有抑制活性,因此,HSP90已成为抗肿瘤药物研发的热门靶点。基于片段的药物设计是HSP90抑制剂开发的重要策略,已发现了众多结构新颖的高效率配体的小分子片段,依据结构信息进行优化,开发了许多具有良好活性的先导物乃至临床候选物。本文分析了一些基于片段方法的HSP90抑制剂开发案例,并基于X线衍射晶体结构信息,综述了这些从片段到先导物乃至候选药的理性优化过程。

Molecular chaperone heat shock protein 90（HSP90） exists in an activated form and over-expresses in tumor cell, thus playing a key role in assisting tumor survival, proliferation, invasion, metastasis and angiogenesis. Natural product geldanamycin and its derivatives were found to target HSP90 Nt-ATP binding site and exhibit inhibitory activities against many tumors in vivo, thus, HSP90 has already become an attractive therapeutic target for anti-cancer drug discovery. Fragment-based drug design has been used as effective strategy for the development of HSP90 inhibitors, and a lot of fragment hits with structural novelty and high ligand efficiency were found, then many highly potent leads and clinical candidates were developed through crystal structure based optimization. This review describes several reported HSP90 inhibitors discovered in a fragment-based approach, and highlights the rational optimization process from fragment to lead compound, and clinical candidate based on the X-ray co-crystal structure of HSP90 and its inhibitor.