The p53-MDM2/MDMX axis - A chemotype perspective.
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.
University of Pittsburgh, Department of Pharmaceutical Science, Drug Discovery Institute, Pittsburgh, PA, USA.
Kareem
K
Khoury
Max Planck Institut für Biochemie, München, Germany.
Grzegorz M
GM
Popowicz
Max Planck Institut für Biochemie, München, Germany.
Tad A
TA
Holak
University of Pittsburgh, Department of Pharmaceutical Science, Drug Discovery Institute, Pittsburgh, PA, USA.
Alexander
A
Dömling