Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains

Bouché, Léa; Christ, Clara D.; Siegel, Stephan; Fernández-Montalván, Amaury E.; Holton, Simon J.; Fedorov, Oleg; Laak, Antonius ter; Sugawara, Tatsuo; Stöckigt, Detlef; Tallant, C.; Bennett, James M.; Monteiro, Octovia; Diaz-Saez, L.; Siejka, Paulina; Meier, Julia; Pütter, Vera; Weiske, Jörg; Müller, Susanne; Huber, Kilian; Hartung, Ingo V.; Haendler, Bernard

doi:10.1021/acs.jmedchem.7b00306

Cited by 58 publications

(53 citation statements)

References 72 publications

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“…BRPF BRD antagonists are well represented by the pan-BRPF chemical probes OF-1 and NI-57, and the two related BRPF1B selective chemical probes PFI-4 and GSK6853 52, 53 . In addition, BAY-299, a dual activity chemical probe for BRPF2 and TAF1(2), has also been developed providing the only currently available chemical tool for family VII 54 . Similarly, compound 34, a dual activity antagonist of TRIM24 and BRPF1B represents the only chemical tool currently developed for TRIM24 55 .…”

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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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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“…Bromodomains share a conserved globular fold and are composed of a left-handed bundle of four α-helices Z, A, B and C. The helices are linked by loops of variable length (ZA and BC loops), which form the hydrophobic acetyllysine (Kac) binding pocket 4 . The acetyllysine recognition of these bromodomains differ mainly due to the variability within their ZA and BC loops 4 .These differences, have also permitted the development of small molecule inhibitors with selectivity for specific bromodomains within the same family [27][28][29][30] .…”

Section: Introductionmentioning

confidence: 99%

The BRPF1 bromodomain is a molecular reader of di-acetyllysine

Juliet

Lubula

Cornilescu

et al. 2020

Preprint

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ABSTRACTBromodomain-containing proteins are often part of chromatin-modifying complexes, and their activity can lead to altered expression of genes that drive cancer, inflammation and neurological disorders in humans. Bromodomain-PHD finger protein 1 (BRPF1) is part of the MOZ (monocytic leukemic zinc-finger protein) HAT (histone acetyltransferase) complex, which is associated with chromosomal translocations known to contribute to the development of acute myeloid leukemia (AML). BRPF1 contains a unique combination of chromatin reader domains including two plant homeodomain (PHD) fingers separated by a zinc knuckle (PZP domain), a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) domain. BRPF1 is known to recruit the MOZ HAT complex to chromatin by recognizing acetylated lysine residues on the N-terminal histone tail region through its bromodomain. However, histone proteins can contain several acetylation modifications on their N-terminus, and it is unknown how additional marks influence bromodomain recruitment to chromatin. Here, we identify the BRPF1 bromodomain as a selective reader of di-acetyllysine modifications on histone H4. We used ITC assays to characterize the binding of di-acetylated histone ligands to the BRPF1 bromodomain and found that the domain binds preferentially to histone peptides H4K5acK8ac and H4K5acK12ac. Analytical ultracentrifugation (AUC) experiments revealed that the monomeric state of the BRPF1 bromodomain coordinates di-acetylated histone ligands. NMR chemical shift perturbation studies, along with binding and mutational analyses, revealed non-canonical regions of the bromodomain-binding pocket that are important for histone tail recognition. Together, our findings provide critical information on how the combinatorial action of post-translational modifications can modulate BRPF1 bromodomain binding and specificity.

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“…Collaborative work between Bayer and the SGC has led to the identification of BAY‐299 ( 48 ), a potent and selective triple inhibitor of BRPF2 (BRPF2 pIC 50 =7.2) and TAF1/TAF1L (TAF1 pIC 50 =8.1) (Figure b) . An initial HTS of ≈3.5 million compounds resulted in potent (BRPF2 pIC 50 =6.3) hit compound 47 , selected for displaying selectivity over BRD4 (BRD4(1) pIC 50 =4.9).…”

Section: Typical Non‐bet Bromodomain Inhibitorsmentioning

confidence: 99%

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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Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains

Cited by 58 publications

References 72 publications

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

The BRPF1 bromodomain is a molecular reader of di-acetyllysine

Advancements in the Development of non‐BET Bromodomain Chemical Probes

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