1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR.
A library of 1,4-benzodiazepine-2,5-diones was screened for binding to the p53-binding domain of HDM2 using Thermofluor, a miniaturized thermal denaturation assay. The hits obtained were shown to bind to HDM2 in the p53-binding pocket using a fluorescence polarization (FP) peptide displacement assay. The potency of the series was optimized, leading to sub-micromolar antagonists of the p53-HDM2 interaction.
Parks
Daniel J
DJ
Johnson and Johnson Pharmaceutical Research and Development, 665 Stockton Drive, Exton, PA 19341, USA.
Lafrance
Louis V
LV
Calvo
Raul R
RR
Milkiewicz
Karen L
KL
Gupta
Varsha
V
Lattanze
Jennifer
J
Ramachandren
Kannan
K
Carver
Theodore E
TE
Petrella
Eugene C
EC
Cummings
Maxwell D
MD
Maguire
Diane
D
Grasberger
Bruce L
BL
Lu
Tianbao
T
D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D005454:Fluorescence Polarization; D006801:Humans; D020128:Inhibitory Concentration 50; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2