Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells.
HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.
Grasberger
Bruce L
BL
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 665 Stockton Drive, Exton, Pennsylvania 19341, USA. bgrasber@prdus.jnj.com
Lu
Tianbao
T
Schubert
Carsten
C
Parks
Daniel J
DJ
Carver
Theodore E
TE
Koblish
Holly K
HK
Cummings
Maxwell D
MD
LaFrance
Louis V
LV
Milkiewicz
Karen L
KL
Calvo
Raul R
RR
Maguire
Diane
D
Lattanze
Jennifer
J
Franks
Carol F
CF
Zhao
Shuyuan
S
Ramachandren
Kannan
K
Bylebyl
Gwendolyn R
GR
Zhang
Marie
M
Manthey
Carl L
CL
Petrella
Eugene C
EC
Pantoliano
Michael W
MW
Deckman
Ingrid C
IC
Spurlino
John C
JC
Maroney
Anna C
AC
Tomczuk
Bruce E
BE
Molloy
Christopher J
CJ
Bone
Roger F
RF
D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051736:Proto-Oncogene Proteins c-mdm2; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000096:biosynthesis
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2