Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery.
Intensive anticancer drug discovery efforts have been made to develop small molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here the structures of the most potent inhibitors bound to MDM2 and MDMX that are based on the new imidazo-indole scaffold. In addition, the structure of the recently reported spiro-oxindole inhibitor bound to MDM2 is described. The structures indicate how the substituents of a small molecule that bind to the three subpockets of the MDM2/X-p53 interaction should be optimized for effective binding to MDM2 and/or MDMX. While the spiro-oxindole inhibitor triggers significant ligand-induced changes in MDM2, the imidazo-indoles share similar binding modes for MDMX and MDM2, but cause only minimal induced-fit changes in the structures of both proteins. Our study includes the first structure of the complex between MDMX and a small molecule and should aid in developing efficient scaffolds for binding to MDMX and/or MDM2.
Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Grzegorz M
GM
Popowicz
Anna
A
Czarna
Siglinde
S
Wolf
Kan
K
Wang
Wei
W
Wang
Alexander
A
Dömling
Tad A
TA
Holak
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008970:Molecular Weight; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D007211:Indoles; D008024:Ligands; D016159:Tumor Suppressor Protein p53; C030374:indole; D051736:Proto-Oncogene Proteins c-mdm2