Khoury Kareem, Popowicz Grzegorz M, Holak Tad A, Dömling Alexander
University of Pittsburgh, Department of Pharmaceutical Science, Drug Discovery Institute, Pittsburgh, PA, USA.
Max Planck Institut für Biochemie, München, Germany.
Medchemcomm. 2011;2:246-260. doi: 10.1039/C0MD00248H.
The protein-protein interaction (PPI) of the tumor suppressor p53 and its negative regulator MDM2 consists of the most intense studied PPI with a group of small molecular weight antagonists described and many more disclosed in patent literature. Due to the Å-level structural insight into p53 interaction with MDM2 there is a reasonable understanding of the requirements of the molecules to bind. In contrast and despite the very close homology and 3-D similarity no potent MDMX antagonist has been disclosed up to date. The current review summarizes the different disclosed chemotypes for MDM2 including a discussion of the cocrystal structures. Structures and approaches to reconstitute functional p53 from mutated p53 are presented. Finally new screening methods and recent biotech deals based on p53 are discussed.
肿瘤抑制因子p53与其负调控因子MDM2之间的蛋白质-蛋白质相互作用（PPI）是研究最为深入的PPI之一，已有一组小分子拮抗剂被报道，专利文献中还披露了更多相关内容。由于对p53与MDM2相互作用有了埃级别的结构洞察，因此对分子结合的要求有了合理的认识。相比之下，尽管MDMX与MDM2具有非常高的同源性和三维相似性，但迄今为止尚未有有效的MDMX拮抗剂被披露。本综述总结了已公开的针对MDM2的不同化学类型，包括对共晶体结构的讨论。还介绍了从突变型p53重构功能性p53的结构和方法。最后，讨论了基于p53的新筛选方法和近期生物技术交易。
