Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432

Philip G. Humphreys; Niall A. Anderson; Paul Bamborough; Andrew Baxter; Chun-wa Chung; Rosa Cookson; Peter D. Craggs; Toryn Dalton; Julie C. L. Fournier; Laurie J. Gordon; Heather F. Gray; Matthew W. Gray; Richard Gregory; David J. Hirst; Craig Jamieson; Katherine L. Jones; Hripsimee Kessedjian; David Lugo; Grant McGonagle; Vipulkumar K. Patel; Christopher Patten; Darren L. Poole; Rab K. Prinjha; Cesar Ramirez-Molina; Inmaculada Rioja; Gail Seal; Kayleigh A. J. Stafford; Rishi R. Shah; Daniel Tape; Natalie H. Theodoulou; Laura R. Tomlinson; Sabri Ukuser; Ian D. Wall; Natalie Wellaway; Gemma White

doi:10.1021/acs.jmedchem.2c01102

Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432

Philip G. Humphreys, Niall A. Anderson, Paul Bamborough, Andrew Baxter, Chun-wa Chung, Rosa Cookson, Peter D. Craggs, Toryn Dalton, Julie C. L. Fournier, Laurie J. Gordon, Heather F. Gray, Matthew W. Gray, Richard Gregory, David J. Hirst, Craig Jamieson, Katherine L. Jones, Hripsimee Kessedjian, David Lugo, Grant McGonagle, Vipulkumar K. PatelChristopher Patten, Darren L. Poole, Rab K. Prinjha, Cesar Ramirez-Molina, Inmaculada Rioja, Gail Seal, Kayleigh A. J. Stafford, Rishi R. Shah, Daniel Tape, Natalie H. Theodoulou, Laura R. Tomlinson, Sabri Ukuser, Ian D. Wall, Natalie Wellaway, Gemma White

Pure And Applied Chemistry

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Abstract

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein–protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure–activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.

Original language	English
Pages (from-to)	15174-15207
Number of pages	34
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	22
Early online date	15 Nov 2022
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01102
Publication status	Published - 24 Nov 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Drug Discovery
Molecular Medicine

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10.1021/acs.jmedchem.2c01102

Humphreys-etal-JMC-Identification-and-optimization-of-a-ligand-efficient-benzoazepinoneAccepted author manuscript, 3.56 MBLicence: Strath_1

Cite this

Humphreys, P. G., Anderson, N. A., Bamborough, P., Baxter, A., Chung, C., Cookson, R., Craggs, P. D., Dalton, T., Fournier, J. C. L., Gordon, L. J., Gray, H. F., Gray, M. W., Gregory, R., Hirst, D. J., Jamieson, C., Jones, K. L., Kessedjian, H., Lugo, D., McGonagle, G., ... White, G. (2022). Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432. Journal of Medicinal Chemistry, 65(22), 15174-15207. https://doi.org/10.1021/acs.jmedchem.2c01102

@article{9b25a073e6ba40668c06f13de3c1f816,

title = "Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432",

abstract = "The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein–protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure–activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.",

keywords = "Drug Discovery, Molecular Medicine",

author = "Humphreys, \{Philip G.\} and Anderson, \{Niall A.\} and Paul Bamborough and Andrew Baxter and Chun-wa Chung and Rosa Cookson and Craggs, \{Peter D.\} and Toryn Dalton and Fournier, \{Julie C. L.\} and Gordon, \{Laurie J.\} and Gray, \{Heather F.\} and Gray, \{Matthew W.\} and Richard Gregory and Hirst, \{David J.\} and Craig Jamieson and Jones, \{Katherine L.\} and Hripsimee Kessedjian and David Lugo and Grant McGonagle and Patel, \{Vipulkumar K.\} and Christopher Patten and Poole, \{Darren L.\} and Prinjha, \{Rab K.\} and Cesar Ramirez-Molina and Inmaculada Rioja and Gail Seal and Stafford, \{Kayleigh A. J.\} and Shah, \{Rishi R.\} and Daniel Tape and Theodoulou, \{Natalie H.\} and Tomlinson, \{Laura R.\} and Sabri Ukuser and Wall, \{Ian D.\} and Natalie Wellaway and Gemma White",

note = "Copyright {\textcopyright} 2022 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.2c01102.",

year = "2022",

month = nov,

day = "24",

doi = "10.1021/acs.jmedchem.2c01102",

language = "English",

volume = "65",

pages = "15174--15207",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "22",

}

Humphreys, PG, Anderson, NA, Bamborough, P, Baxter, A, Chung, C, Cookson, R, Craggs, PD, Dalton, T, Fournier, JCL, Gordon, LJ, Gray, HF, Gray, MW, Gregory, R, Hirst, DJ, Jamieson, C, Jones, KL, Kessedjian, H, Lugo, D, McGonagle, G, Patel, VK, Patten, C, Poole, DL, Prinjha, RK, Ramirez-Molina, C, Rioja, I, Seal, G, Stafford, KAJ, Shah, RR, Tape, D, Theodoulou, NH, Tomlinson, LR, Ukuser, S, Wall, ID, Wellaway, N & White, G 2022, 'Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432', Journal of Medicinal Chemistry, vol. 65, no. 22, pp. 15174-15207. https://doi.org/10.1021/acs.jmedchem.2c01102

Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432. / Humphreys, Philip G.; Anderson, Niall A.; Bamborough, Paul et al.
In: Journal of Medicinal Chemistry, Vol. 65, No. 22, 24.11.2022, p. 15174-15207.

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

TY - JOUR

T1 - Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432

AU - Humphreys, Philip G.

AU - Anderson, Niall A.

AU - Bamborough, Paul

AU - Baxter, Andrew

AU - Chung, Chun-wa

AU - Cookson, Rosa

AU - Craggs, Peter D.

AU - Dalton, Toryn

AU - Fournier, Julie C. L.

AU - Gordon, Laurie J.

AU - Gray, Heather F.

AU - Gray, Matthew W.

AU - Gregory, Richard

AU - Hirst, David J.

AU - Jamieson, Craig

AU - Jones, Katherine L.

AU - Kessedjian, Hripsimee

AU - Lugo, David

AU - McGonagle, Grant

AU - Patel, Vipulkumar K.

AU - Patten, Christopher

AU - Poole, Darren L.

AU - Prinjha, Rab K.

AU - Ramirez-Molina, Cesar

AU - Rioja, Inmaculada

AU - Seal, Gail

AU - Stafford, Kayleigh A. J.

AU - Shah, Rishi R.

AU - Tape, Daniel

AU - Theodoulou, Natalie H.

AU - Tomlinson, Laura R.

AU - Ukuser, Sabri

AU - Wall, Ian D.

AU - Wellaway, Natalie

AU - White, Gemma

N1 - Copyright © 2022 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.2c01102.

PY - 2022/11/24

Y1 - 2022/11/24

N2 - The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein–protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure–activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.

AB - The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein–protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure–activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.

KW - Drug Discovery

KW - Molecular Medicine

U2 - 10.1021/acs.jmedchem.2c01102

DO - 10.1021/acs.jmedchem.2c01102

M3 - Article

SN - 0022-2623

VL - 65

SP - 15174

EP - 15207

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -

Humphreys PG, Anderson NA, Bamborough P, Baxter A, Chung C, Cookson R et al. Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432. Journal of Medicinal Chemistry. 2022 Nov 24;65(22):15174-15207. Epub 2022 Nov 15. doi: 10.1021/acs.jmedchem.2c01102

Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432

Abstract

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Keywords

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