Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities

Chekler, Eugene L. Piatnitski; Pellegrino, Jessica; Lanz, Thomas A.; Denny, R. Aldrin; Flick, Andrew C.; Coe, Jotham W.; Langille, Jonathan; Basak, Arindrajit; Liu, Shenping; Stock, Ingrid A.; Sahasrabudhe, Parag V.; Bonin, Paul D.; Lee, Kevin; Pletcher, Mathew T.; Jones, Lyn H.

doi:10.1016/j.chembiol.2015.10.013

Cited by 50 publications

(51 citation statements)

References 38 publications

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“…PF-CBP1 (Fig. 4) is another selective inhibitor of the CREBBP/P300 bromodomain, which downregulates a number of inflammatory genes in macrophages and the RSG4 gene in neurons 149 Finally, another CREBBP/P300 bromodomain inhibitor, CPI-637 (Fig. 4), 150 was recently reported to have high potency in vitro and selectivity over other bromodomains.…”

Section: Bromodomain Inhibitorsmentioning

confidence: 99%

Bromodomain inhibitors and cancer therapy: From structures to applications

2016

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Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are “writers,” “erasers,” or “readers” of histone modification marks are common. Bromodomains are “readers” that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. In recent years, there has been increasing interest in developing small molecules that can target specific bromodomains. First, this has helped clarify biological functions of bromodomain-containing proteins. Secondly, it opens a new front for combatting cancer. In this review we will describe the structures and mechanisms associated with Bromodomain and Extra-Terminal motif (BET) inhibitors and non-BET inhibitors, their current status of development, and their promising role as anti-cancer agents.

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Section: Bromodomain Inhibitorsmentioning

confidence: 99%

Bromodomain inhibitors and cancer therapy: From structures to applications

2016

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“…Blocking this interaction with a cyclic p53-K382 peptide, blocks p53 induction of p21 expression [46]. Relatively recently, several high affinity small molecule ligands for the p300/CBP bromodomains have been developed [47–52]. Each of these was shown to induce some cellular phenotype, and several were crystallized bound to the p300/CBP [50–52].…”

Section: Multi-domain Regulation Of P300/cbpmentioning

confidence: 99%

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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“…The structurally related PF-CBP1 (11) was reported by researchers at Pfizer as a dual chemical probe for CREBBP and EP300 [48]. Although less potent than SGC-CBP30 (10), PF-CBP1 (11) is more selective with CREBBP K d : 190 nM and >105 fold selectivity against BRD4.…”

Section: Crebbp and Ep300mentioning

confidence: 96%

Clinical progress and pharmacology of small molecule bromodomain inhibitors

Theodoulou¹,

Tomkinson

Prinjha

et al. 2016

Current Opinion in Chemical Biology

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Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer, inflammation, embryonic development and neurological disorders.

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Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities

Cited by 50 publications

References 38 publications

Bromodomain inhibitors and cancer therapy: From structures to applications

Bromodomain inhibitors and cancer therapy: From structures to applications

Allosteric regulation of epigenetic modifying enzymes

Clinical progress and pharmacology of small molecule bromodomain inhibitors

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