Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B

abstract: ...Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the nucleolar remodeling complex (NoRC) that regulates the expression of noncoding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here we report the development of GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor of BAZ2A and BAZ2B bromodomains as well as the inactive control compound GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants ( K D ) of 136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures demonstrated a canonical acetyl-lysine competitive binding mode. Cellular activity was demonstrated using fluorescent recovery after photobleaching (FRAP) monitoring displacement of GFP-BAZ2A from acetylated chromatin. A pharmacokinetic study in mice showed that GSK2801 had reasonable in vivo exposure after oral dosing, with modest clearance and reasonable plasma stability. Thus, GSK2801 represents a versatile tool compound for cellular and in vivo studies to understand the role of BAZ2 bromodomains in chromatin biology.

...J Med Chem J. Med. Chem jm jmcmar Journal of Medicinal Chemistry 0022-2623 1520-4804 American Chemical Society 25799074 4770311 10.1021/acs.jmedchem.5b00209 Article Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B Chen Peiling Chaikuad Apirat Bamborough Paul Bantscheff Marcus # Bountra Chas Chung Chun-wa Fedorov Oleg Grandi Paola # Jung David Lesniak Robert Lindon Matthew Mller Susanne Philpott Martin Prinjha Rab Rogers

..., provided the author and source are cited. Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the nucleolar remodeling complex (NoRC) that regulates the expression of noncoding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here we report the development of GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor of BAZ2A and BAZ2B bromodomains as well as the inactive control compound GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants ( K D ) of 136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures demonstrated a canonical acetyl-lysine competitive binding mode. Cellular activity was demonstrated using fluorescent recovery

... can be used as an additional independent validation tool has recently been published by our group in collaboration with an academic collaborator. 21 BAZ1A, BAZ1B, BAZ2A, and BAZ2B constitute a family of evolutionarily conserved and ubiquitously expressed proteins with conserved domain structure including PHD and bromodomain histone tail reader motifs. 22 BAZ2A is a component of the nucleolar remodeling complex (NoRC), a member of the imitation switch chromatin remodeling complexes (ISWI), 23 which play a role in regulating the expression of noncoding RNAs and in the formation of repressive heterochromatin in particular at centromeres and telomeres. 24 , 25 Association of BAZ2A with acetylated histone tails is mediated by its bromodomain. 26 Recently, high expression levels of BAZA have been reported in prostate cancer, and the protein may serve as a marker for metastatic potential. 27 Little is known about the BAZ2B subtype. However, single nucleotide polymorphisms (SNPs) in the BAZ2B gene locus have been associated with sudden cardiac death. High expression levels of BAZ2B have been associated with poor outcome of pediatric B cell acute lymphoblastic leukemia (B-ALL). 28 X-ray crystal structures of the BAZ2A/B bromodomains showed a shallow acetyl-lysine binding pocket, and they were predicted to be among the least druggable members of the protein family. 29 We therefore felt that identification of inhibitors for the BAZ2A/B bromodomains would be an interesting indicator of the

... compound 1 bound to BRD2 (PDB ID: 4A9I) revealed that the methyl ketone is serving as an acetyl lysine mimetic (Figure 2 A). Compound 1 was modeled into the acetyl lysine binding site of BAZ2B (Figure 2 A). The channel that accommodates the indolizine R1 substituent appears wider in BAZ2B, suggesting that modification in this region will modulate selectivity. To facilitate the optimization of the indolizine hit, we cocrystallized an early representative compound ( 2 ) with BAZ2B (Figure 2 B). Compound

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Gene: BAZ2B - bromodomain adjacent to zinc finger domain, 2B - (NCBI)

Protein : 4nra

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