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抑制蛋白-蛋白相互作用(PPI)的小分子药物向来是新药研发的难题,雅培公司创制的venetoclax是第一个真正意义上的PPI抑制剂。该药研发20年,历尽曲折与风险。本文从药物化学的视角简要介绍其研发过程。Venetoclax的研制涉及多种技术方法,包括用核磁共振(SAR by NMR),基于片段的药物发现(FBDD),X-射线晶体学指导基于蛋白结构的分子设计以及集中库的设计等。研发中两次更改靶标,由单一的靶标Bcl-x L蛋白改换成双靶标Bcl-x L/Bcl-2,最后聚焦为Bcl-2蛋白,彰显出研发的巨大风险性,见证了确证靶标的可药性(druggability)贯穿于从先导物到临床试验的全过程。作为口服治疗慢性淋巴白血病的药物,Venetoclax的创新性还表现出化学结构突破了“类药5规则”的限制,分子量为882的化合物足以屏蔽掉两个蛋白的结合热域(hot spots)也体现了构建化学结构的成功。
Small molecule drugs that inhibit protein-protein interaction (PPI) have always been a challenge for drug discovery, and venetoclax, created by Abbott, was the first true PPI inhibitor. The drug R & D for 20 years, experienced twists and turns and risk. This article briefly describes its R & D process from the perspective of medicinal chemistry. The development of Venetoclax involves a variety of technical approaches including nuclear magnetic resonance (SAR by NMR), fragment based drug discovery (FBDD), X-ray crystallography directed molecular structure design based on protein structure, and design of centralized libraries. R & D twice changed the target, from a single target Bcl-x L protein to double target Bcl-x L / Bcl-2, and finally focused on the Bcl-2 protein, highlighting the great risk of development, witnessed the confirmation target The druggability runs through the whole process from the leader to the clinical trial. As a drug for oral treatment of chronic lymphatic leukemia, Venetoclax’s innovation also shows that the chemical structure breaks through the limitations of the “Class 5 rules” and compounds with a molecular weight of 882 are sufficient to mask the hot spots of both proteins. Also reflects the success of the construction of chemical structure.