Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain

Law, Robert P.; Atkinson, Sophie; Bamborough, Paul; Chung, Chun‐wa; Demont, Emmanuel H.; Gordon, Laurie J.; Lindon, Matthew; Prinjha, Rab K.; Watson, Allan J. B.; Hirst, David

doi:10.1021/acs.jmedchem.7b01666

Cited by 104 publications

(94 citation statements)

References 87 publications

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“…These peptides also display dramatically greater selectivity for BD1s over BD2s (and vice versa) than has been observed previously. The most selective small molecules have affinities that differ by a factor of ∼10 to 300 (28,(31)(32)(33); in comparison, we describe selectivities of up to ∼10,000-fold or more. Moreover, specificities of up to ∼10-fold were observed in some cases within the BD1 or BD2 subtypes.…”

Section: Rapid-derived Cyclic Peptides Are the Highest-affinity And Mostmentioning

confidence: 93%

Cyclic peptides can engage a single binding pocket through highly divergent modes

Patel

Walport

Walshe

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic peptide library screening technologies show immense promise for identifying drug leads and chemical probes for challenging targets. However, the structural and functional diversity encoded within such libraries is largely undefined. We have systematically profiled the affinity, selectivity, and structural features of library-derived cyclic peptides selected to recognize three closely related targets: the acetyllysine-binding bromodomain proteins BRD2, -3, and -4. We report affinities as low as 100 pM and specificities of up to 106-fold. Crystal structures of 13 peptide–bromodomain complexes reveal remarkable diversity in both structure and binding mode, including both α-helical and β-sheet structures as well as bivalent binding modes. The peptides can also exhibit a high degree of structural preorganization. Our data demonstrate the enormous potential within these libraries to provide diverse binding modes against a single target, which underpins their capacity to yield highly potent and selective ligands.

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Section: Rapid-derived Cyclic Peptides Are the Highest-affinity And Mostmentioning

confidence: 93%

Cyclic peptides can engage a single binding pocket through highly divergent modes

Patel

Walport

Walshe

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Conversely, mutations of the corresponding asparagine residue in SMARCA2 bromodomain, ac entral component of the SWI/SNF chromatin-remodelling complex, did not affect fluorescence recovery,s uggesting an alternative binding interaction, at least in the context investigated. [29] Akey question in the function of the BET bromodomains has been whether the first bromodomain and the second bromodomain have different functions,a nd consequently, whether selective inhibition would result in different phenotypes.Prior to the publication of ligands that show selectivity for either the first or second BET bromodomains, [54] Baud et al took an elegant approach to address this question. To expand the current understanding of the complex processes revolving around the BET bromodomains,t hey engineered controlled selectivity using the bump-and-hole approach (Figure 4), [31b] which was originally pioneered by Shokat to develop selective kinase inhibitors.…”

Section: Applications Of Methods For Cellular Target Engagement In Comentioning

confidence: 99%

Chemical Epigenetics: The Impact of Chemical and Chemical Biology Techniques on Bromodomain Target Validation

et al. 2019

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Epigenetics is currently the focus of intense research interest across a broad range of disciplines due to its importance in a multitude of biological processes and disease states. Epigenetic functions result partly from modification of the nucleobases in DNA and RNA, and/or post‐translational modifications of histone proteins. These modifications are dynamic, with cellular machinery identified to modulate and interpret the marks. Our focus is on bromodomains, which bind to acetylated lysine residues. Progress in the study of bromodomains, and the development of bromodomain ligands, has been rapid. These advances have been underpinned by many disciplines, but chemistry and chemical biology have undoubtedly played a significant role. Herein, we review the key chemistry and chemical biology approaches that have furthered our study of bromodomains, enabled the development of bromodomain ligands, and played a critical role in the validation of bromodomains as therapeutic targets.

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“…These peptides also display dramatically greater selectivity for BD1s over BD2s (and vice versa) than has been observed previously. The most selective small molecules reported prefer BD1 over BD2 domains by a factor of ~10-50-fold; in comparison, we describe selectivities of up to ~10,000-fold or more 31,32 . Moreover, specificities of up to ~10-fold were observed in some cases within the BD1 or BD2 subtypes.…”

Section: Rapid-derived Cyclic Peptides Are the Highest-affinity And Mmentioning

confidence: 59%

Cyclic peptides can engage a single binding pocket through multiple, entirely divergent modes

Patel

et al. 2019

Preprint

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Cyclic peptide display screening techniques can identify drug leads and biological probes with exceptional affinity and specificity. To date, however, the structural and functional diversity encoded in such peptide libraries remains unexplored. We have used the Random nonstandard Peptide Integrated Discovery (RaPID) system to develop cyclic peptide inhibitors of several acetyllysine-binding bromodomains from the Bromodomain and Extra-Terminal domain (BET) family of epigenetic regulators. These peptides have very high affinities for their targets and exhibit extraordinary selectivity (up to 10 6 -fold), making them the highest-affinity and most specific BET-binding molecules discovered to date. Crystal structures of 13 distinct peptide-bromodomain complexes, which all target the acetyllysine-binding pocket, reveal remarkable diversity in both peptide structure and binding mode, and include both α-helical and β-sheet type structures. The peptides can exhibit a high degree of structural preorganization and bivalent binding of two BDs by one peptide was common, flagging the potential for a new direction in inhibitor design that could bring stronger discrimination between BET-family paralogues. Our data demonstrate for the first time the enormous potential held in these libraries to provide a wide array of modes against a single target, maximizing the opportunity to attain high potency and specificity ligands to a wide variety of proteins.

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Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain

Cited by 104 publications

References 87 publications

Cyclic peptides can engage a single binding pocket through highly divergent modes

Cyclic peptides can engage a single binding pocket through highly divergent modes

Chemical Epigenetics: The Impact of Chemical and Chemical Biology Techniques on Bromodomain Target Validation

Cyclic peptides can engage a single binding pocket through multiple, entirely divergent modes

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