Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction

Gianni Chessari, Ian R. Hardcastle, Jong Sook Ahn, Burcu Anil, Elizabeth Anscombe, Ruth H. Bawn, Luke D. Bevan, Timothy J. Blackburn, Ildiko Buck, Celine Cano, Benoit Carbain, Juan Castro, Ben Cons, Sarah J. Cully, Jane A. Endicott, Lynsey Fazal, Bernard T. Golding, Roger J. Griffin, Karen Haggerty, Suzannah J. HarnorKeisha Hearn, Stephen Hobson, Rhian S. Holvey, Steven Howard, Claire E. Jennings, Christopher N. Johnson, John Lunec, Duncan C. Miller, David R. Newell, Martin E. M. Noble, Judith Reeks, Charlotte H. Revill, Christiane Riedinger, Jeffrey D. St. Denis, Emiliano Tamanini, Huw Thomas, Neil T. Thompson, Mladen Vinković, Stephen R. Wedge, Pamela A. Williams, Nicola E. Wilsher, Bian Zhang, Yan Zhao

Research output: Contribution to journalArticlepeer-review

Abstract

Inhibition of murine double minute 2 (MDM2)-p53 protein–protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
Original languageEnglish
Pages (from-to)4071-4088
JournalJournal of Medicinal Chemistry
Volume64
Issue number7
DOIs
Publication statusPublished - 8 Apr 2021

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