Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells

Bruce L. Grasberger, Tianbao Lu, Carsten Schubert, Daniel J. Parks, Theodore E. Carver, Holly K. Koblish, Maxwell D. Cummings, Louis V. LaFrance, Karen L. Milkiewicz, Raul R. Calvo, Diane Maguire, Jennifer Lattanze, Carol F. Franks, Shuyuan Zhao, Kannan Ramachandren, Gwendolyn R. Bylebyl, Marie Zhang, Carl L. Manthey, Eugene C. Petrella, Michael W. PantolianoIngrid C. Deckman, John C. Spurlino, Anna C. Maroney, Bruce E. Tomczuk, Christopher J. Molloy, Roger F. Bone

Research output: Contribution to journalArticle

359 Scopus citations

Abstract

HDM2 binds to an α-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 α-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.

Original languageEnglish (US)
Pages (from-to)909-912
Number of pages4
JournalJournal of medicinal chemistry
Volume48
Issue number4
DOIs
StatePublished - Feb 24 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Grasberger, B. L., Lu, T., Schubert, C., Parks, D. J., Carver, T. E., Koblish, H. K., Cummings, M. D., LaFrance, L. V., Milkiewicz, K. L., Calvo, R. R., Maguire, D., Lattanze, J., Franks, C. F., Zhao, S., Ramachandren, K., Bylebyl, G. R., Zhang, M., Manthey, C. L., Petrella, E. C., ... Bone, R. F. (2005). Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. Journal of medicinal chemistry, 48(4), 909-912. https://doi.org/10.1021/jm049137g