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

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.

• Authors: 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 Harnor, Keisha 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 7 Pg. 4071-4088 (04 08 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33761253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Isoindoles
• TP53 protein, human
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology)
• Bone Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Crystallography, X-Ray
• Drug Stability
• Female
• Humans
• Isoindoles (chemical synthesis, metabolism, pharmacology)
• Macaca fascicularis
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Microsomes, Liver (metabolism)
• Molecular Structure
• Osteosarcoma (drug therapy)
• Protein Binding
• Protein Multimerization (drug effects)
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Structure-Activity Relationship
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays
• Mice