Design and synthesis of potent and selective inhibitors of BRD7 and BRD9 bromodomains

Hay, Duncan; Rogers, Catherine; Fedorov, Oleg; Tallant, C.; Martin, Sarah; Monteiro, Octovia; Müller, Susanne; Knapp, S.; Schofield, Christopher J.; Brennan, P.E.

doi:10.1039/c5md00152h

Cited by 66 publications

(90 citation statements)

References 32 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In green, are bromodomains inhibited by PFI-3 [92] and Compound 17 [91]; in blue are bromodomains inhibited by LP99 [106], I-BRD9 [107], Compound 28 [108], BI-7273(1) and BI-9564(2) [109]. ( B ) Dissociation constants or Kd (nM) of each small molecule to their respective targets are tabulated.…”

Section: Figurementioning

confidence: 99%

Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities

Pierre

Kadoch

2017

Current Opinion in Genetics & Development

142

133

View full text Add to dashboard Cite

Mammalian SWI/SNF (BAF) chromatin remodeling complexes orchestrate a diverse set of chromatin alterations which impact transcriptional output. Recent whole-exome sequencing efforts have revealed that the genes encoding subunits of mSWI/SNF complexes are mutated in over 20% of cancers, spanning a wide range of tissue types. The majority of mutations result in loss of subunit protein expression, implicating mSWI/SNF subunits as tumor suppressors. mSWI/SNF-deficient cancers remain a therapeutic challenge, owing to a lack of potent and selective agents which target complexes or unique pathway dependencies generated by mSWI/SNF subunit perturbations. Here, we review the current landscape of mechanistic insights and emerging therapeutic opportunities for human malignancies driven by mSWI/SNF complex perturbation.

show abstract

Section: Figurementioning

confidence: 99%

Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities

Pierre

Kadoch

2017

Current Opinion in Genetics & Development

142

133

View full text Add to dashboard Cite

show abstract

“…Highly homologous bromodomain containing protein 7 (BRD7) is a component of the SWI/SNF polybromoassociated BAF (PBAF) complex and has been proposed as a tumor suppressor [30]. Within the last year, there have been several publications focussing on BRD9 and dual BRD7/9 chemical probe development [31][32][33].…”

Section: Brd7 and Brd9mentioning

confidence: 99%

Clinical progress and pharmacology of small molecule bromodomain inhibitors

Theodoulou¹,

Tomkinson

Prinjha

et al. 2016

Current Opinion in Chemical Biology

View full text Add to dashboard Cite

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.

show abstract

“…Although their overall sequence similarity is low (36%), their BrDs share 72% sequence identity. [34] Fragment based screening lead to quinolone LP99 (BRD9 IC 50 = 99 nM, BRD7 IC 50 = 909 nM) that elucidated the role of BRD7/9 in inflammatory pathways. Structure-based drug discovery afforded thienopyridone I-BRD9 (BRD9 K D = 50 nM) with 700-fold selectivity over the BET family and 200-fold over BRD7, and was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways.…”

Section: Chemical Modulators For Acetyl-lysine Binding Domainsmentioning

confidence: 99%

Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation

Zaware

Zhou

2017

Current Opinion in Chemical Biology

View full text Add to dashboard Cite

Site-specific lysine acetylation and methylation on histones are critical post-translational modifications (PTMs) that govern ordered gene transcription in chromatin. Mis-regulation of these histone PTM-mediated processes has been shown to be associated with human diseases. Since the 2010 landmark reports of small molecules (+)-JQ1 and I-BET762 that target the acetyl-lysine ‘reader’ Bromodomain and Extra Terminal domain (BET) proteins, there have been relentless efforts to develop epigenetic therapy with small molecules to modulate molecular interactions of epigenome reader domain proteins with PTMs. In addition to BET, the other emerging targets include non-BET acetyl- and methyl-lysine reader domains. This review covers the key chemical modulators of the aforementioned epigenome reader proteins.

show abstract

Design and synthesis of potent and selective inhibitors of BRD7 and BRD9 bromodomains

Abstract: We describe potent and selective inhibitors of the BRD7 and BRD9 bromodomains intended for use as chemical probes to elucidate the biological roles of BRD7 and BRD9 in cells.

Cited by 66 publications

References 32 publications

Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities

Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities

Clinical progress and pharmacology of small molecule bromodomain inhibitors

Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation

Contact Info

Product

Resources

About