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Structure-based design of potent and orally active isoindolinone inhibitors of MDM2-p53 protein–protein interaction

DOI: 10.1021/acs.jmedchem.0c02188 DOI Help

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

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: March 2021

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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 07/04/2021 09:08

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)