Pan-SMARCA/PB1 Bromodomain Inhibitors and Their Role in Regulating Adipogenesis

Abstract

Accessibility of the human genome is modulated by the ATP-driven SWI/SNF chromatin remodeling multiprotein complexes BAF (BRG1/BRM-associated factor) and PBAF (polybromo-associated BAF factor), which involves reading of acetylated histone tails by the bromodomain-containing proteins SMARCA2 (BRM), SMARCA4 (BRG1), and polybromo-1. Dysregulation of chromatin remodeling leads to aberrant cell proliferation and differentiation. Here, we have characterized a set of potent and cell-active bromodomain inhibitors with pan-selectivity for canonical family VIII bromodomains. Targeted SWI/SNF bromodomain inhibition blocked the expression of key genes during adipogenesis, including the transcription factors PPARγ and C/EBPα, and impaired the differentiation of 3T3-L1 murine fibroblasts into adipocytes. Our data highlight the role of SWI/SNF bromodomains in adipogenesis and provide a framework for the development of SWI/SNF bromodomain inhibitors for indirect targeting of key transcription factors regulating cell differentiation.

Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy

“…The residue numbering in the BRD9 structure is based on the canonical isoform in UniProt entry Q9H8M2, which differs from the numbering in the original PDB entry that is based on an isoform lacking the first 116 residues. C – E Crystal structures of BRD subfamily VIII members with bound inhibitors (PDB entries 5DKD, 6ZS4, 6ZNV) reveal a similar overall inhibitor binding mode [ 90 , 93 ]. F Crystal structure of the ternary complex of SMARCA4 and the E3 ubiquitin ligase VHL bound to PROTAC ACBI1, showing that the complex is stabilised by additional protein–protein interactions (PDB entry 6HR2) [ 104 ].…”

“…Due to the lack of chemical stability of PFI-3 in cellular systems over longer time periods, several other SMARCA2/4 BRD inhibitors were developed [ 91 , 92 ]. However, only one of them, SGC-SMARCA-BRDVIII (compound 22 ) [ 93 ], which has been recently developed based on a patent [ 94 ], met chemical probe criteria in terms of potency (Figs. 3d and 4b ).…”

“…Due to the high sequence conservation in the acetyl-lysine binding site of BRD subfamily VIII, most of the PB1-BRD inhibitors show selectivity for the fifth PB1 bromodomain and for SMARCA2/4 BRDs; the recently published compound 32 , however, also showed activity on the second and third bromodomain of PB1 (Figs. 3e and 4b ) [ 90 , 91 , 93 , 94 ]. Only one selective ligand with low affinity for the fifth PB1-BRD has been developed so far [ 95 ].…”

“…5 ) as well as in the development of selective and potent bromodomain inhibitors for directly targeting SWI/SNF function (Fig. 4 ) [ 80 , 89 , 90 , 93 ]. It came somewhat as a surprise, though, that these bromodomain inhibitors failed to display significant antiproliferative effects.…”

Targeting the Bromodomain of BRG-1/BRM Subunit of the SWI/SNF Complex Increases the Anticancer Activity of Temozolomide in Glioblastoma

“…PFI-3 is a small-molecule inhibitor of the bromodomains (BRDs) of the BRM/BRG1 subunits [ 13 , 14 ]. The BRDs of these subunits read histone acetylation marks, while the ATPase domains propel DNA along the histone surface.…”