Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction.
Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line.
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: andrea.vaupel@novartis.com.
Andrea
A
Vaupel
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
Guido
G
Bold
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
Alain
A
De Pover
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
Thérèse
T
Stachyra-Valat
Joanna Hergovich
JH
Lisztwan
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
Joanna
J
Hergovich-Lisztwan
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
Joerg
J
Kallen
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
Keiichi
K
Masuya
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: pascal.furet@novartis.com.
Pascal
P
Furet
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D060066:Protein Interaction Maps / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D007093:Imidazoles; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
MDM2; Protein–protein interaction inhibitors; Structure-based design; p53