Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe

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

doi:10.1021/acs.jmedchem.6b01566

Cited by 77 publications

(80 citation statements)

References 67 publications

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“…This trans acetylation activation model is similar to a proposal for the activation of H3 acetylation when p300 is incubated with nucleosomes already containing penta-acetylated H4 tails or at least one H4 tail acetylation site [54]. The recent reports of potent Gcn5 bromodomain selective ligands [60,61] offer promise to more deeply probe this allostery.…”

Section: Catalytic Regulation Of Gcn5 By Its Bromodomainsupporting

confidence: 73%

Allosteric regulation of epigenetic modifying enzymes

Zucconi

Cole

2017

Current Opinion in Chemical Biology

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Epigenetic enzymes including histone modifying enzymes are key regulators of gene expression in normal and disease processes. Many drug development strategies to target histone modifying enzymes have focused on ligands that bind to enzyme active sites, but allosteric pockets offer potentially attractive opportunities for therapeutic development. Recent biochemical studies have revealed roles for small molecule and peptide ligands binding outside of the active sites in modulating the catalytic activities of histone modifying enzymes. Here we highlight several examples of allosteric regulation of epigenetic enzymes and discuss the biological significance of these findings.

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Section: Catalytic Regulation Of Gcn5 By Its Bromodomainsupporting

confidence: 73%

Allosteric regulation of epigenetic modifying enzymes

Zucconi

Cole

2017

Current Opinion in Chemical Biology

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“…Compound 10 was also accompanied by GSK4028( 11)a ne nantiomeric negative control (PCAF pIC 50 = 4.9). [34] Similarly, l-Moses (13), another selective and potent PCAF/ GCN5 inhibitor,h as recently been reported as ac hemical probe for PCAF/GCN5 (Figure 4c,f). [35] The triazolopyridazine scaffold,f ound in promiscuous bromodomain inhibitor bromosporine, [36] was used as as tartingp oint.…”

Section: Pcaf/gcn5supporting

confidence: 58%

Advancements in the Development of non‐BET Bromodomain Chemical Probes

et al. 2019

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The bromodomain and extra terminal (BET) family of bromodomain‐containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high‐quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non‐BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non‐BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non‐BET bromodomains as tractable therapeutic targets.

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“…The dual PCAF/GCN5 chemical probe L-Moses showed good potency for these two highly related bromodomains (K D of 126 nM and 600 nM respectively, determined by ITC) 36 . GSK4027 offers an alternative chemotype to antagonize the BRDs in these two targets with improved potency (K D 1,4 nM determined by BROMOscan ® for both BRDs) 37 . Early lead molecules for bromodomains of CECR2 and FALZ were discovered by screening a series of triazolophthalazines 38 .…”

Section: Resultsmentioning

confidence: 99%

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

Heidenreich

Zhou

et al. 2018

Preprint

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SummaryBromodomains (BRDs) are evolutionary conserved epigenetic protein interaction modules which recognize ("read") acetyl-lysine, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective tool small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan® and demonstrate the utility of the set using studies of muscle cell differentiation and triple negative breast cancer (TNBC). We identified cross talk between histone acetylation and the glycolytic pathway resulting in a vulnerability of TNBC cell lines to inhibition of BRPF2/3 BRDs under conditions of glucose deprivation or GLUT1 inhibition. This chemical probe set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.

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Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe

Cited by 77 publications

References 67 publications

Allosteric regulation of epigenetic modifying enzymes

Allosteric regulation of epigenetic modifying enzymes

Advancements in the Development of non‐BET Bromodomain Chemical Probes

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

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