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 Bevan, Timothy J. Blackburn, Ildiko M. Buck, Céline Cano, Benoît Carbain, Juan Castro, Benjamin D. Cons, Sarah J. Cully, Jane Endicott, Lynsey Fazal, Bernard T. Golding, Roger J. Griffin, Karen Haggerty, Suzannah J. Harnor, Keisha Hearn, Stephen J. Hobson, Rhian S. Holvey, Steven Howard, Claire Jennings, Christopher N. Johnson, John Lunec, Duncan C. Miller, David R. Newell, M.E.M. Noble, Judith Reeks, Charlotte Revill, Christiane Riedinger, Jeffrey D. St. Denis, Emiliano Tamanini, Huw D. Thomas, Neil T. Thompson, M. Vinković, Stephen R. Wedge, Pamela A. Williams, Nicola E. Wilsher, Bian Zhang, Yan Zhao
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.