Discovery of a novel bromodomain and extra terminal domain (BET) protein inhibitor, I-BET282E, suitable for clinical progression

Katherine L. Jones; Dominic M. Beaumont; Sharon G. Bernard; Rino A. Bit; Simon P. Campbell; Chun-wa Chung; Leanne Cutler; Emmanuel H. Demont; Kate Dennis; Laurie Gordon; James R. Gray; Michael V. Haase; Antonia J. Lewis; Scott McCleary; Darren J. Mitchell; Susanne M. Moore; Nigel Parr; Olivia J. Robb; Nicholas Smithers; Peter E. Soden; Colin J. Suckling; Simon Taylor; Ann L. Walker; Robert J. Watson; Rab K. Prinjha

doi:10.1021/acs.jmedchem.1c00855

Discovery of a novel bromodomain and extra terminal domain (BET) protein inhibitor, I-BET282E, suitable for clinical progression

Katherine L. Jones, Dominic M. Beaumont, Sharon G. Bernard, Rino A. Bit, Simon P. Campbell, Chun-wa Chung, Leanne Cutler, Emmanuel H. Demont, Kate Dennis, Laurie Gordon, James R. Gray, Michael V. Haase, Antonia J. Lewis, Scott McCleary, Darren J. Mitchell, Susanne M. Moore, Nigel Parr, Olivia J. Robb, Nicholas Smithers, Peter E. SodenColin J. Suckling, Simon Taylor, Ann L. Walker, Robert J. Watson, Rab K. Prinjha

Pure And Applied Chemistry

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

Abstract

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.

Original language	English
Pages (from-to)	12200-12227
Number of pages	28
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	16
Early online date	13 Aug 2021
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00855
Publication status	Published - 26 Aug 2021

Keywords

bromodomain
BET
protein inhibitors
extra terminal domain
proteins
oncology
immuno-inflammatory areas
clinical studies
peptides
rodent models
inhibitors
inhibition

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10.1021/acs.jmedchem.1c00855

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Jones, K. L., Beaumont, D. M., Bernard, S. G., Bit, R. A., Campbell, S. P., Chung, C., Cutler, L., Demont, E. H., Dennis, K., Gordon, L., Gray, J. R., Haase, M. V., Lewis, A. J., McCleary, S., Mitchell, D. J., Moore, S. M., Parr, N., Robb, O. J., Smithers, N., ... Prinjha, R. K. (2021). Discovery of a novel bromodomain and extra terminal domain (BET) protein inhibitor, I-BET282E, suitable for clinical progression. Journal of Medicinal Chemistry, 64(16), 12200-12227. https://doi.org/10.1021/acs.jmedchem.1c00855

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title = "Discovery of a novel bromodomain and extra terminal domain (BET) protein inhibitor, I-BET282E, suitable for clinical progression",

abstract = "The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies. ",

keywords = "bromodomain, BET, protein inhibitors, extra terminal domain, proteins, oncology, immuno-inflammatory areas, clinical studies, peptides, rodent models, inhibitors, inhibition",

author = "Jones, {Katherine L.} and Beaumont, {Dominic M.} and Bernard, {Sharon G.} and Bit, {Rino A.} and Campbell, {Simon P.} and Chun-wa Chung and Leanne Cutler and Demont, {Emmanuel H.} and Kate Dennis and Laurie Gordon and Gray, {James R.} and Haase, {Michael V.} and Lewis, {Antonia J.} and Scott McCleary and Mitchell, {Darren J.} and Moore, {Susanne M.} and Nigel Parr and Robb, {Olivia J.} and Nicholas Smithers and Soden, {Peter E.} and Suckling, {Colin J.} and Simon Taylor and Walker, {Ann L.} and Watson, {Robert J.} and Prinjha, {Rab K.}",

year = "2021",

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doi = "10.1021/acs.jmedchem.1c00855",

language = "English",

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Jones, KL, Beaumont, DM, Bernard, SG, Bit, RA, Campbell, SP, Chung, C, Cutler, L, Demont, EH, Dennis, K, Gordon, L, Gray, JR, Haase, MV, Lewis, AJ, McCleary, S, Mitchell, DJ, Moore, SM, Parr, N, Robb, OJ, Smithers, N, Soden, PE, Suckling, CJ, Taylor, S, Walker, AL, Watson, RJ & Prinjha, RK 2021, 'Discovery of a novel bromodomain and extra terminal domain (BET) protein inhibitor, I-BET282E, suitable for clinical progression', Journal of Medicinal Chemistry, vol. 64, no. 16, pp. 12200-12227. https://doi.org/10.1021/acs.jmedchem.1c00855

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AU - Jones, Katherine L.

AU - Beaumont, Dominic M.

AU - Bernard, Sharon G.

AU - Bit, Rino A.

AU - Campbell, Simon P.

AU - Chung, Chun-wa

AU - Cutler, Leanne

AU - Demont, Emmanuel H.

AU - Dennis, Kate

AU - Gordon, Laurie

AU - Gray, James R.

AU - Haase, Michael V.

AU - Lewis, Antonia J.

AU - McCleary, Scott

AU - Mitchell, Darren J.

AU - Moore, Susanne M.

AU - Parr, Nigel

AU - Robb, Olivia J.

AU - Smithers, Nicholas

AU - Soden, Peter E.

AU - Suckling, Colin J.

AU - Taylor, Simon

AU - Walker, Ann L.

AU - Watson, Robert J.

AU - Prinjha, Rab K.

PY - 2021/8/26

Y1 - 2021/8/26

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AB - The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.

KW - bromodomain

KW - BET

KW - protein inhibitors

KW - extra terminal domain

KW - proteins

KW - oncology

KW - immuno-inflammatory areas

KW - clinical studies

KW - peptides

KW - rodent models

KW - inhibitors

KW - inhibition

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SN - 0022-2623

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 16

ER -

Discovery of a novel bromodomain and extra terminal domain (BET) protein inhibitor, I-BET282E, suitable for clinical progression

Abstract

Keywords

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