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. 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

doi:10.1021/acs.jmedchem.0c02188

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

SHLS Life Sciences

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	4071-4088
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	7
DOIs	https://doi.org/10.1021/acs.jmedchem.0c02188
Publication status	Published - 8 Apr 2021

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10.1021/acs.jmedchem.0c02188

https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02188

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Chessari, G., Hardcastle, I. R., Ahn, J. S., Anil, B., Anscombe, E., Bawn, R. H., Bevan, L. D., Blackburn, T. J., Buck, I., Cano, C., Carbain, B., Castro, J., Cons, B., Cully, S. J., Endicott, J. A., Fazal, L., Golding, B. T., Griffin, R. J., Haggerty, K., ... Zhao, Y. (2021). Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction. Journal of Medicinal Chemistry, 64(7), 4071-4088. https://doi.org/10.1021/acs.jmedchem.0c02188

@article{ea969575dbf74f868fc0e724349a7a86,

title = "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.",

author = "Gianni Chessari and Hardcastle, {Ian R.} and Ahn, {Jong Sook} and Burcu Anil and Elizabeth Anscombe and Bawn, {Ruth H.} and Bevan, {Luke D.} and Blackburn, {Timothy J.} and Ildiko Buck and Celine Cano and Benoit Carbain and Juan Castro and Ben Cons and Cully, {Sarah J.} and Endicott, {Jane A.} and Lynsey Fazal and Golding, {Bernard T.} and Griffin, {Roger J.} and Karen Haggerty and Harnor, {Suzannah J.} and Keisha Hearn and Stephen Hobson and Holvey, {Rhian S.} and Steven Howard and Jennings, {Claire E.} and Johnson, {Christopher N.} and John Lunec and Miller, {Duncan C.} and Newell, {David R.} and Noble, {Martin E. M.} and Judith Reeks and Revill, {Charlotte H.} and Christiane Riedinger and {St. Denis}, {Jeffrey D.} and Emiliano Tamanini and Huw Thomas and Thompson, {Neil T.} and Mladen Vinkovi{\'c} and Wedge, {Stephen R.} and Williams, {Pamela A.} and Wilsher, {Nicola E.} and Bian Zhang and Yan Zhao",

year = "2021",

month = apr,

day = "8",

doi = "10.1021/acs.jmedchem.0c02188",

language = "English",

volume = "64",

pages = "4071--4088",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "7",

}

Chessari, G, Hardcastle, IR, Ahn, JS, Anil, B, Anscombe, E, Bawn, RH, Bevan, LD, Blackburn, TJ, Buck, I, Cano, C, Carbain, B, Castro, J, Cons, B, Cully, SJ, Endicott, JA, Fazal, L, Golding, BT, Griffin, RJ, Haggerty, K, Harnor, SJ, Hearn, K, Hobson, S, Holvey, RS, Howard, S, Jennings, CE, Johnson, CN, Lunec, J, Miller, DC, Newell, DR, Noble, MEM, Reeks, J, Revill, CH, Riedinger, C, St. Denis, JD, Tamanini, E, Thomas, H, Thompson, NT, Vinković, M, Wedge, SR, Williams, PA, Wilsher, NE, Zhang, B & Zhao, Y 2021, 'Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction', Journal of Medicinal Chemistry, vol. 64, no. 7, pp. 4071-4088. https://doi.org/10.1021/acs.jmedchem.0c02188

TY - JOUR

T1 - Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction

AU - Chessari, Gianni

AU - Hardcastle, Ian R.

AU - Ahn, Jong Sook

AU - Anil, Burcu

AU - Anscombe, Elizabeth

AU - Bawn, Ruth H.

AU - Bevan, Luke D.

AU - Blackburn, Timothy J.

AU - Buck, Ildiko

AU - Cano, Celine

AU - Carbain, Benoit

AU - Castro, Juan

AU - Cons, Ben

AU - Cully, Sarah J.

AU - Endicott, Jane A.

AU - Fazal, Lynsey

AU - Golding, Bernard T.

AU - Griffin, Roger J.

AU - Haggerty, Karen

AU - Harnor, Suzannah J.

AU - Hearn, Keisha

AU - Hobson, Stephen

AU - Holvey, Rhian S.

AU - Howard, Steven

AU - Jennings, Claire E.

AU - Johnson, Christopher N.

AU - Lunec, John

AU - Miller, Duncan C.

AU - Newell, David R.

AU - Noble, Martin E. M.

AU - Reeks, Judith

AU - Revill, Charlotte H.

AU - Riedinger, Christiane

AU - St. Denis, Jeffrey D.

AU - Tamanini, Emiliano

AU - Thomas, Huw

AU - Thompson, Neil T.

AU - Vinković, Mladen

AU - Wedge, Stephen R.

AU - Williams, Pamela A.

AU - Wilsher, Nicola E.

AU - Zhang, Bian

AU - Zhao, Yan

PY - 2021/4/8

Y1 - 2021/4/8

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.0c02188

DO - 10.1021/acs.jmedchem.0c02188

M3 - Article

SN - 0022-2623

VL - 64

SP - 4071

EP - 4088

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 7

ER -

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

Abstract

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