The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition

Natalie H. Theodoulou, Paul Bamborough, Andrew J. Bannister, Isabelle Becher, Rino A. Bit, Ka Hing Che, Chun-wa Chung, Antje Dittmann, Gerard Drewes, David H. Drewy, Laurie Gordon, Paola Grandi, Melanie Leveridge, Matthew Lindon, Anne-Marie Michon, Judit Molnar, Samuel C. Robson, Nicholas C. O. Tomkinson, Tony Kouzarides, Rab K. Prinjha & 1 others Philip G. Humphreys

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.
LanguageEnglish
Pages1425-1439
Number of pages15
JournalJournal of Medicinal Chemistry
Volume59
Issue number4
Early online date9 Apr 2015
DOIs
Publication statusPublished - 25 Feb 2016

Fingerprint

Proteins
Acetylation
Oncology
Post Translational Protein Processing
Histones
Lysine
Chromatin
Anti-Inflammatory Agents
Genes
Phenotype

Keywords

  • I‑BRD9
  • bromodomain
  • BRD9
  • protein acylation

Cite this

Theodoulou, N. H., Bamborough, P., Bannister, A. J., Becher, I., Bit, R. A., Che, K. H., ... Humphreys, P. G. (2016). The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition. Journal of Medicinal Chemistry, 59(4), 1425-1439. https://doi.org/10.1021/acs.jmedchem.5b00256
Theodoulou, Natalie H. ; Bamborough, Paul ; Bannister, Andrew J. ; Becher, Isabelle ; Bit, Rino A. ; Che, Ka Hing ; Chung, Chun-wa ; Dittmann, Antje ; Drewes, Gerard ; Drewy, David H. ; Gordon, Laurie ; Grandi, Paola ; Leveridge, Melanie ; Lindon, Matthew ; Michon, Anne-Marie ; Molnar, Judit ; Robson, Samuel C. ; Tomkinson, Nicholas C. O. ; Kouzarides, Tony ; Prinjha, Rab K. ; Humphreys, Philip G. / The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 4. pp. 1425-1439.
@article{ee7121c97ba84c86a292ecef9cdcbd77,
title = "The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition",
abstract = "Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.",
keywords = "I‑BRD9, bromodomain, BRD9, protein acylation",
author = "Theodoulou, {Natalie H.} and Paul Bamborough and Bannister, {Andrew J.} and Isabelle Becher and Bit, {Rino A.} and Che, {Ka Hing} and Chun-wa Chung and Antje Dittmann and Gerard Drewes and Drewy, {David H.} and Laurie Gordon and Paola Grandi and Melanie Leveridge and Matthew Lindon and Anne-Marie Michon and Judit Molnar and Robson, {Samuel C.} and Tomkinson, {Nicholas C. O.} and Tony Kouzarides and Prinjha, {Rab K.} and Humphreys, {Philip G.}",
year = "2016",
month = "2",
day = "25",
doi = "10.1021/acs.jmedchem.5b00256",
language = "English",
volume = "59",
pages = "1425--1439",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",

}

Theodoulou, NH, Bamborough, P, Bannister, AJ, Becher, I, Bit, RA, Che, KH, Chung, C, Dittmann, A, Drewes, G, Drewy, DH, Gordon, L, Grandi, P, Leveridge, M, Lindon, M, Michon, A-M, Molnar, J, Robson, SC, Tomkinson, NCO, Kouzarides, T, Prinjha, RK & Humphreys, PG 2016, 'The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition' Journal of Medicinal Chemistry, vol. 59, no. 4, pp. 1425-1439. https://doi.org/10.1021/acs.jmedchem.5b00256

The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition. / Theodoulou, Natalie H.; Bamborough, Paul; Bannister, Andrew J. ; Becher, Isabelle; Bit, Rino A. ; Che, Ka Hing; Chung, Chun-wa; Dittmann, Antje; Drewes, Gerard; Drewy, David H.; Gordon, Laurie; Grandi, Paola; Leveridge, Melanie; Lindon, Matthew; Michon, Anne-Marie; Molnar, Judit; Robson, Samuel C.; Tomkinson, Nicholas C. O.; Kouzarides, Tony; Prinjha, Rab K. ; Humphreys, Philip G.

In: Journal of Medicinal Chemistry, Vol. 59, No. 4, 25.02.2016, p. 1425-1439.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition

AU - Theodoulou, Natalie H.

AU - Bamborough, Paul

AU - Bannister, Andrew J.

AU - Becher, Isabelle

AU - Bit, Rino A.

AU - Che, Ka Hing

AU - Chung, Chun-wa

AU - Dittmann, Antje

AU - Drewes, Gerard

AU - Drewy, David H.

AU - Gordon, Laurie

AU - Grandi, Paola

AU - Leveridge, Melanie

AU - Lindon, Matthew

AU - Michon, Anne-Marie

AU - Molnar, Judit

AU - Robson, Samuel C.

AU - Tomkinson, Nicholas C. O.

AU - Kouzarides, Tony

AU - Prinjha, Rab K.

AU - Humphreys, Philip G.

PY - 2016/2/25

Y1 - 2016/2/25

N2 - Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.

AB - Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.

KW - I‑BRD9

KW - bromodomain

KW - BRD9

KW - protein acylation

UR - http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00256

U2 - 10.1021/acs.jmedchem.5b00256

DO - 10.1021/acs.jmedchem.5b00256

M3 - Article

VL - 59

SP - 1425

EP - 1439

JO - Journal of Medicinal Chemistry

T2 - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 4

ER -