Discovery of a PCAF Bromodomain Chemical Probe

Moustakim, Moses; Clark, Peter G. K.; Trulli, Laura; Arriba, Ángel L. Fuentes de; Ehebauer, M.T.; Chaikuad, A.; Murphy, Emma J.; Mendez‐Johnson, Jacqui; Daniels, Danette L.; Hou, Chun-Feng David; Lin, Yu‐Hui; Walker, John R.; Hui, Raymond; Yang, Hongbing; Dorrell, Lucy; Rogers, Catherine; Monteiro, Octovia; Fedorov, Oleg; Huber, Kilian; Knapp, Stefan; Heer, Jag; Dixon, Darren J.; Brennan, P.E.

doi:10.1002/anie.201610816

Cited by 67 publications

(48 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

Section: Catalytic Regulation Of Gcn5 By Its Bromodomainsupporting

confidence: 73%

Allosteric regulation of epigenetic modifying enzymes

Zucconi

Cole

2017

Current Opinion in Chemical Biology

View full text Add to dashboard Cite

show abstract

“…Exemplary inhibitors of readers,writers, and erasers. l-Moses [15] and UNC1215 [13] are inhibitors of theB RD of PCAFa nd methyl-lysine binding MBT domain of L3MBTL3 respectively. A-485 [19] is aC BP/p300 histonea cetyltransferase (HAT) inhibitor, and EPZ015666 [16] inhibits the methyltransferases PRMT5.V orinostat (SAHA) is ac linically used HDAC inhibitor,a nd compound 48 [24] is an inhibitor ofthe 2-oxoglutarated ependent KDM5d emethylases.…”

Section: Resultsmentioning

confidence: 99%

“…There have been many recent reports of inhibitors for reader, [6][7][8][9][10][11][12][13][14][15] writer, [16][17][18][19] and, in some cases, eraser domains. [20][21][22][23][24] Bromodomains (BRD) are acetyl-lysine bindingd omains, for which numerous inhibitors have been developed.…”

Section: Introductionmentioning

confidence: 99%

Identifying small molecule binding sites for epigenetic proteins at domain-domain interfaces

Bowkett¹,

Talon²,

Tallant³

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket. Examination of X-ray structures of multiple domains involved in recognizing and modifying post-translational histone marks using the SiteMap algorithm identified potential binding sites at domain-domain interfaces. For the tandem plant homeodomain-bromodomain of SP100C, a potential inter-domain site identified computationally was validated experimentally by the discovery of ligands by X-ray crystallographic fragment screening.

show abstract

“…[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. Introduction of small amine groups was used to exploit the characteristically narrow PCAF ZA channel and to establish the acid/base interaction with Glu761 discussed previously,f rom whichs electivity over the BET subfamily can be attributed.…”

Section: Pcaf/gcn5mentioning

confidence: 99%

Advancements in the Development of non‐BET Bromodomain Chemical Probes

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

Discovery of a PCAF Bromodomain Chemical Probe

Cited by 67 publications

References 37 publications

Allosteric regulation of epigenetic modifying enzymes

Allosteric regulation of epigenetic modifying enzymes

Identifying small molecule binding sites for epigenetic proteins at domain-domain interfaces

Advancements in the Development of non‐BET Bromodomain Chemical Probes

Contact Info

Product

Resources

About