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

Lookup NU author(s): Dr Ian HardcastleORCiD, Dr Ruth Bawn, Dr Tim Blackburn, Dr Celine CanoORCiD, Dr Sarah Cully, Emeritus Professor Bernard Golding, Professor Roger Griffin, Dr Karen Haggerty, Dr Suzannah HarnorORCiD, Dr Stephen Hobson, Dr Claire Jennings, Professor John LunecORCiD, Duncan MillerORCiD, Professor Martin NobleORCiD, Charlotte Revill, Huw ThomasORCiD, Professor Steve Wedge, Dr Bian Zhang



This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Chemical Society, 2021.

For re-use rights please refer to the publisher's terms and conditions.


Disruption of the MDM2-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe the use of rational, structure-guided, design in the discovery of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, QM ligand-based design and metabolite identification all contributed towards 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.

Publication metadata

Author(s): Chessari G, Hardcastle IR, Ahn JS, Anil B, Anscome E, Bawn RH, Bevan LD, Blackburn TJ, Buck I, Cano C, Carbain B, Castro J, Cons B, Cully SJ, St Denis J, Endicott JA, Fazal L, Golding BT, Griffin RJ, Haggerty K, Harnor S, Hearn K, Hobson S, Holvey RS, Howard S, Jennings C, Johnson CN, Lunec J, Miller DC, Newell DR, Noble MEM, Reeks J, Revill CH, Riedinger C, Tamanini E, Thomas H, Thompson NT, Vinkovic M, Wedge SR, Williams PA, Wilsher N, Zhang B, Zhao Y

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2021

Volume: 64

Issue: 7

Pages: 4071-4088

Online publication date: 24/03/2021

Acceptance date: 03/03/2021

Date deposited: 26/03/2021

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.0c02188


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