Histone deacetylase inhibitors (HDACi) induce potent anti-inflammatory responses when used to treat inflammatory diseases. Suberoylanilide hydroxamic acid (SAHA), a pan-HDACi, decreases pro-inflammatory cytokine levels and attenuates cytokine storm in sepsis; however, its toxicity profile toward immune cells has limited its use as a sepsis therapeutic. Here, we developed a modification to SAHA by para-hydroxymethylating the capping group to generate SAHA-OH. We discovered that SAHA-OH provides a favorable improvement to the toxicity profile compared to SAHA. SAHA-OH significantly reduced primary macrophage apoptosis and splenic B cell death as well as mitigated organ damage using a lipopolysaccharide (LPS)-induced endotoxemia mouse model. Furthermore, SAHA-OH retained anti-inflammatory responses similar to SAHA as measured by reductions in LPS-induced proinflammatory cytokine secretions in vitro and in vivo. These effects were attributed to a decreased selectivity of HDAC1, 2, 3, 8 and an increased selectivity for HDAC6 for SAHA-OH as determined by IC50 values. Our results support the potential for SAHA-OH to modulate acute proinflammatory responses while mitigating SAHA-associated drug toxicity for use in the treatment of inflammation-associated diseases and conditions.
© 2022 American Chemical Society.