Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe

Erin Bradley; Lucia Fusani; Chun-wa Chung; Peter D. Craggs; Emmanuel H. Demont; Philip G. Humphreys; Darren J. Mitchell; Alexander Phillipou; Inmaculada Rioja; Rishi R. Shah; Christopher R. Wellaway; Rab K.  Prinjha; David S. Palmer; William J. Kerr; Marc Reid; Ian D. Wall; Rosa Cookson

doi:10.1021/acs.jmedchem.3c00906

Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe

Erin Bradley, Lucia Fusani, Chun-wa Chung, Peter D. Craggs, Emmanuel H. Demont, Philip G. Humphreys, Darren J. Mitchell, Alexander Phillipou, Inmaculada Rioja, Rishi R. Shah, Christopher R. Wellaway, Rab K. Prinjha, David S. Palmer, William J. Kerr, Marc Reid, Ian D. Wall, Rosa Cookson

Pure And Applied Chemistry

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

4 Citations (Scopus)

22 Downloads (Pure)

Abstract

Small molecule mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain dataset through a lipophilic efficiency lens, which enabled identification of a BD1 domain biased benzimidazole series. Structure guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

Original language	English
Pages (from-to)	15728-15749
Number of pages	22
Journal	Journal of Medicinal Chemistry
Volume	66
Issue number	23
Early online date	15 Nov 2023
DOIs	https://doi.org/10.1021/acs.jmedchem.3c00906
Publication status	Published - 14 Dec 2023

Keywords

bromodomain
BET
BD1
chemical probe
lipophilic efficiency

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10.1021/acs.jmedchem.3c00906Licence: CC BY 4.0

Bradley-etal-JMC-2023-Structure-guided-design-of-a-domain-selective-bromodomain-and-extra-terminal-N-terminalFinal published version, 10.1 MBLicence: CC BY 4.0

Accelerated Discovery and Development of New Medicines: Prosperity Partnership for a Healthier Nation
Kerr, W., Brown, C., Florence, A., Jamieson, C., Johnston, B., Murphy, J., Palmer, D. & Tomkinson, N.
EPSRC (Engineering and Physical Sciences Research Council)
1/01/19 → 30/09/24
Project: Research

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Bradley, E., Fusani, L., Chung, C., Craggs, P. D., Demont, E. H., Humphreys, P. G., Mitchell, D. J., Phillipou, A., Rioja, I., Shah, R. R., Wellaway, C. R., Prinjha, R. K., Palmer, D. S., Kerr, W. J., Reid, M., Wall, I. D., & Cookson, R. (2023). Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe. Journal of Medicinal Chemistry, 66(23), 15728-15749. https://doi.org/10.1021/acs.jmedchem.3c00906

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title = "Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe",

abstract = "Small molecule mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain dataset through a lipophilic efficiency lens, which enabled identification of a BD1 domain biased benzimidazole series. Structure guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.",

keywords = "bromodomain, BET, BD1, chemical probe, lipophilic efficiency",

author = "Erin Bradley and Lucia Fusani and Chun-wa Chung and Craggs, {Peter D.} and Demont, {Emmanuel H.} and Humphreys, {Philip G.} and Mitchell, {Darren J.} and Alexander Phillipou and Inmaculada Rioja and Shah, {Rishi R.} and Wellaway, {Christopher R.} and Prinjha, {Rab K.} and Palmer, {David S.} and Kerr, {William J.} and Marc Reid and Wall, {Ian D.} and Rosa Cookson",

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doi = "10.1021/acs.jmedchem.3c00906",

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publisher = "American Chemical Society",

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Bradley, E, Fusani, L, Chung, C, Craggs, PD, Demont, EH, Humphreys, PG, Mitchell, DJ, Phillipou, A, Rioja, I, Shah, RR, Wellaway, CR, Prinjha, RK, Palmer, DS , Kerr, WJ , Reid, M, Wall, ID & Cookson, R 2023, 'Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe', Journal of Medicinal Chemistry, vol. 66, no. 23, pp. 15728-15749. https://doi.org/10.1021/acs.jmedchem.3c00906

TY - JOUR

T1 - Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe

AU - Bradley, Erin

AU - Fusani, Lucia

AU - Chung, Chun-wa

AU - Craggs, Peter D.

AU - Demont, Emmanuel H.

AU - Humphreys, Philip G.

AU - Mitchell, Darren J.

AU - Phillipou, Alexander

AU - Rioja, Inmaculada

AU - Shah, Rishi R.

AU - Wellaway, Christopher R.

AU - Prinjha, Rab K.

AU - Palmer, David S.

AU - Kerr, William J.

AU - Reid, Marc

AU - Wall, Ian D.

AU - Cookson, Rosa

PY - 2023/12/14

Y1 - 2023/12/14

N2 - Small molecule mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain dataset through a lipophilic efficiency lens, which enabled identification of a BD1 domain biased benzimidazole series. Structure guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

AB - Small molecule mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain dataset through a lipophilic efficiency lens, which enabled identification of a BD1 domain biased benzimidazole series. Structure guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

KW - bromodomain

KW - BET

KW - BD1

KW - chemical probe

KW - lipophilic efficiency

U2 - 10.1021/acs.jmedchem.3c00906

DO - 10.1021/acs.jmedchem.3c00906

M3 - Article

SN - 0022-2623

VL - 66

SP - 15728

EP - 15749

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -

Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe

Abstract

Keywords

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Accelerated Discovery and Development of New Medicines: Prosperity Partnership for a Healthier Nation

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