Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140.

BACKGROUND: SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn's disease (CD), suggesting a role in inflammation. RESULTS: We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa. CONCLUSIONS: This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine-2,3-dioxygenase (IDO) as Potential Target for Anticancer Activity.

Natural quinones, often linked with cellular oxidation processes, exhibit pronounced biological activity. In particular, the structurally unique isothiazolonaphthoquinone aulosirazole, isolated from blue-green alga, possesses selective antitumor cytotoxicity, although its mechanism of action is unknown. The first synthesis of aulosirazole uses a route centered upon a late-stage regioselective Diels-Alder reaction. The structurally related natural product pronqodine A, an inhibitor of prostaglandin release, and analogues thereof, were also prepared for comparison. Biological evaluation of the compounds identified one potential target as the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO). The isothiazoloquinones are also efficient substrates for the human quinone reductase NQO1, and undergo intracellular NQO1-dependent redox cycling resulting in the generation of reactive oxygen species, and at lower doses have the potential to alter the ratio of intracellular oxidized to reduced pyridine nucleotides.