Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe

Philip G. Humphreys; Paul Bamborough; Chun-wa Chung; Peter D. Craggs; Laurie Gordon; Paola Grandi; Thomas G. Hayhow; Jameed Hussain; Katherine L. Jones; Matthew Lindon; Anne-Marie Michon; Jessica F. Renaux; Colin J. Suckling; David F. Tough; Rab K. Prinjha

doi:10.1021/acs.jmedchem.6b01566

Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe

Philip G. Humphreys^*, Paul Bamborough, Chun-wa Chung, Peter D. Craggs, Laurie Gordon, Paola Grandi, Thomas G. Hayhow, Jameed Hussain, Katherine L. Jones, Matthew Lindon, Anne-Marie Michon, Jessica F. Renaux, Colin J. Suckling, David F. Tough, Rab K. Prinjha

^*Corresponding author for this work

Pure And Applied Chemistry

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

68 Citations (Scopus)

Abstract

P300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.

Original language	English
Pages (from-to)	695-709
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	2
Early online date	9 Jan 2017
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01566
Publication status	Published - 26 Jan 2017

Keywords

cell membrane permeability
histone acetyltransferases
membranes

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Humphreys, P. G., Bamborough, P., Chung, C., Craggs, P. D., Gordon, L., Grandi, P., Hayhow, T. G., Hussain, J., Jones, K. L., Lindon, M., Michon, A.-M., Renaux, J. F., Suckling, C. J., Tough, D. F., & Prinjha, R. K. (2017). Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe. Journal of Medicinal Chemistry, 60(2), 695-709. https://doi.org/10.1021/acs.jmedchem.6b01566

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title = "Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe",

abstract = "P300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.",

keywords = "cell membrane permeability, histone acetyltransferases, membranes",

author = "Humphreys, {Philip G.} and Paul Bamborough and Chun-wa Chung and Craggs, {Peter D.} and Laurie Gordon and Paola Grandi and Hayhow, {Thomas G.} and Jameed Hussain and Jones, {Katherine L.} and Matthew Lindon and Anne-Marie Michon and Renaux, {Jessica F.} and Suckling, {Colin J.} and Tough, {David F.} and Prinjha, {Rab K.}",

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month = jan,

day = "26",

doi = "10.1021/acs.jmedchem.6b01566",

language = "English",

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Humphreys, PG, Bamborough, P, Chung, C, Craggs, PD, Gordon, L, Grandi, P, Hayhow, TG, Hussain, J, Jones, KL, Lindon, M, Michon, A-M, Renaux, JF, Suckling, CJ, Tough, DF & Prinjha, RK 2017, 'Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe', Journal of Medicinal Chemistry, vol. 60, no. 2, pp. 695-709. https://doi.org/10.1021/acs.jmedchem.6b01566

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AU - Humphreys, Philip G.

AU - Bamborough, Paul

AU - Chung, Chun-wa

AU - Craggs, Peter D.

AU - Gordon, Laurie

AU - Grandi, Paola

AU - Hayhow, Thomas G.

AU - Hussain, Jameed

AU - Jones, Katherine L.

AU - Lindon, Matthew

AU - Michon, Anne-Marie

AU - Renaux, Jessica F.

AU - Suckling, Colin J.

AU - Tough, David F.

AU - Prinjha, Rab K.

PY - 2017/1/26

Y1 - 2017/1/26

N2 - P300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.

AB - P300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.

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KW - histone acetyltransferases

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IS - 2

ER -

Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe

Abstract

Keywords

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