Several classes of small molecules binding tightly into MDM2 have been described, the most prominent being Nutlins.
Mysteriously, the small molecules binding MDM2 do not bind the closely related second p53 regulator protein MDM4, despite very high sequence and structure homology, especially in the p53 binding site. Now, two groups at the Max Planck Institute of Biochemistry and the University of Pittsburgh could shed light on this mystery by solving the first cocrystal structure of a small molecule binding into the MDM4 p53 interface (2010CellCycle1111).
The scaffold of indoloimidazoles was independently discovered by a group at the University of Pittsburgh and NOVARTIS. It could be efficiently synthesized by a one-pot multicomponent reaction from readily available starting materials and is, therefore, especially suitable for fast and efficient optimization.
Recent evidence implies that the combined use of MDM2 and MDM4 antagonists in cancer cells expressing wild-type p53 should activate p53 more effectively than agents that only antagonize MDM2, resulting in more profound anti-tumour activity. For example, the very aggressive brain tumour glioblastoma multiforme regularly shows MDM2 and MDM4 gene amplification and overexpression.
The structural similarity of MDM2 and MDM4 and the understanding of differences and commonalities of the receptor with Å resolution should now help to design small molecular weight dual-action antagonists.