The bromodomain and extra-terminal domain (BET) family
of proteins
are readers which specifically recognize histone-acetylated lysine
residues. Each BET bromodomain protein contains two highly homologous
domains: the first bromodomain (BD1) and the second bromodomain (BD2).
Pan-BET bromodomain inhibition is a potential therapy for various
cancers and immune-inflammatory diseases, but only few reported inhibitors
show selectivity within the BET family. Herein, we identified a series
of benzo[cd]indol-2(1H)-ones and
pyrrolo[4,3,2-de]quinolin-2(1H)-ones
with good selectivity for BET BD1. Through structure-based optimization,
highly active and selective compounds are ultimately obtained. The
representative compounds are the first reported inhibitors with selectivity
more than 100-fold for BRD4(1) over BRD4(2). Among them, we further
show that 68 (LT052) mediates BRD4/NF-κB/NLRP3
signaling inflammatory pathways with comparable protein expression
and significantly improves symptoms of gout arthritis in a rat model.
Therefore, selective pharmacological modulation of individual bromodomains
could represent a strategy for the treatment of acute gouty arthritis.
Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKβ activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression of Arid1a-deficient tumors. Mechanistically, inflammatory cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via β-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKβ/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression.
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