Development of Hydrazide-Based HDAC6 Selective Inhibitors for Treating NLRP3 Inflammasome-Related Diseases

Previously, we found that hydrazide can serve as zinc binding groups for selective HDAC6 inhibitors and identified the first hydrazide-based HDAC6 inhibitor, <b>35m</b>, which exhibited modest isoform selectivity. This study aimed to improve the HDAC6 selectivity of <b>35m</b>, thereby reducing its side effects. Extensive structure-activity relationship studies revealed that the introduction of fluorine atoms at the 2 and 5 positions of the linker phenyl ring in compound <b>35m</b> significantly enhanced its HDAC6 selectivity while maintaining its potency. The representative compound <b>9m</b> demonstrated an IC₅₀ of 0.021 μM against HDAC6, exhibiting at least 335-fold selectivity over other isoforms, along with favorable pharmacokinetic properties and improved safety profiles. Compound <b>9m</b> inhibits the activation of NLRP3 inflammasome and significantly alleviates symptoms in multiple NLRP3 inflammasome-related disease models, including acute peritoneal, inflammatory bowel disease, and psoriasis. This study enriches the design strategies for selective HDAC6 inhibitors and provides a lead compound for NLRP3 inflammasome-related diseases.