MDM2-p53 interaction inhibitors Library

ChemDiv’s Library of Inhibitors of MDM2-p53 Protein-Protein Interaction contains 22,319 compounds.

ChemDiv has developed a new library of drug-like compounds specifically designed as inhibitors of the MDM2-p53 protein-protein interaction (PPI) that target and modulate reactions between MDM2 and the p53 protein, playing critical role in tumor development. The MDM2-p53 PPI is a critical target in drug discovery, particularly in cancer therapy. MDM2 is a negative regulator of p53, a tumor suppressor protein, and their interaction leads to the degradation of p53, diminishing its tumor-suppressing activities. Inhibiting the MDM2-p53 PPI can stabilize and activate p53, thereby restoring its ability to control cell cycle progression and induce apoptosis in cancer cells. Therefore, drugs that disrupt this interaction offer a promising strategy for treating cancers where p53 is inactivated by overexpression of MDM2. Therefore, developing MDM2-p53 interaction inhibitors is a significant focus in oncological drug research, aiming to reactivate p53’s tumor-suppressive functions in cancer cells. 

The library was built with the use of ChemDiv’s in-house structural biology insights, molecular modeling and simulation, and virtual screening. Our library utilizes novel chemistries and medicinal chemistry techniques of filtering and ranking potential hit molecules. A key 'druggable' 'hot spots' in this library is characterized by specific topological features of the MDM2-p53 interactions. For instance, the cocrystal structure shows that three amino acid residues of p53 (Trp23, Leu26, and Phe19) are essential for hydrophobic bonding with MDM2. Additionally, the cocrystal structures of already known small molecules bound to MDM2 validate the importance of targeting these three hydrophobic regions to effectively disrupt the MDM2-p53 PPI.

ChemDiv has implemented multiple in silico screening methods and specific spatial PPI-related data in designing the sub-libraries inside this compound set. Sub-libraries are centered on scaffolds projecting side chain functionalities with distances and angular properties akin to those in the MDM2-interacting motif of p53.