PROTACHDAC6 degrader7 is an orally active, potent, and selective PROTAC degrader targeting histone deacetylase 6 (HDAC6) with an IC50 of 118 nM. It degrades both the catalytic domain and the zinc finger ubiquitin-binding domain of HDAC6. Furthermore, PROTACHDAC6 degrader7 inhibits the assembly and activation of the NLRP3 inflammasome and blocks the NF-κB signaling pathway, leading to reduced transcription and release of key inflammatory factors. It also decreases the mRNA levels of NLRP3, pro-IL-1β, TNF-α, and IL-6. This compound is useful for research in inflammatory bowel disease (IBD).

PROTAC HDAC6 degrader 7 (Compound 22f) exhibits a potent, concentration-dependent HDAC6 degradation activity (DC 50 = 13.4 nM) in MV4-11 cells at concentrations of 0-2 μM over 12 hours. At 25-200 nM for 12 hours, it causes slight degradation of IKZF1 only at 200 nM, with no effect on GSPT1. The compound shows high specificity for HDAC6 with an IC 50 of 118 nM and exhibits no significant inhibition on other HDAC subtypes at 10 μM. At 0.5 μM for 0-24 hours, it induces HDAC6 degradation in MV4-11 cells starting within 3 hours and reaching equilibrium in 12 hours, a process reversible by both CRBN ligands and proteasome inhibitors, indicating a CRBN-mediated ubiquitin-proteasome pathway mechanism. Additionally, a concentration-dependent half-maximal effective concentration (DC 50) of 9.20 nM is observed for time-dependent degradation of HDAC6 in J774A.1 cells (0-6 μM, 0-24 hours). The compound also significantly inhibits IL-1β expression in LPS/ATP-stimulated J774A.1 cells in a concentration-dependent manner (1.4-1000 nM, 8 hours) and reduces levels of mature IL-1β and p20 at lower concentrations (40-200 nM, 8 hours), while downregulating intracellular NLRP3 and pro-IL-1β protein expression at higher concentrations. It dose-dependently decreases mRNA levels of NLRP3, pro-IL-1β, TNF-α, and IL-6 in LPS-induced J774A.1 cells (0.2-1 μM).

PROTAC HDAC6 degrader 7 (Compound 22f) administered orally at a dosage of 2-10 mg/kg once daily for 9 days effectively alleviates acute colitis induced by Dextran sulfate sodium salt (MW 5000) (DSS) in mice. It improves core symptoms, such as weight loss, diarrhea, and bloody stool, along with pathological damage, including colon shortening and tissue inflammatory infiltration.