PROTACHDAC degrader-2 is a selective PROTAC degrader of class IIb HDACs, exhibiting DC50 values of 13 nM for HDAC6 and 29 nM for HDAC10. It shows low cytotoxicity in both hematologic and solid tumor cell lines, making it useful for chemical knockdown of class IIb HDACs.

HDAC6 (human):13 nM (DC50)

PROTAC HDAC degrader-2 (Compound AP1) exhibits inhibitory effects on HDAC6 and HDAC10, with IC50 values of 0.04 μM and 0.022 μM, respectively, in fluorescent enzyme inhibition assays using substrates Z-Lys(Ac)-AMC or Ac-spermidine-AMC. It shows similar stability to Tubastatin A in human plasma (50-1000 nM, 0-1440 min). In MM.1S cells, it induces sustained, proteasome-dependent degradation of HDAC6 and HDAC10, and similar degradation is observed in MCF-7 cells (1-5 μM, 24 h). At 1 μM concentration, no significant degradation of HDAC1, HDAC4, HDAC7, or HDAC8 occurs in MM.1S cells over 24 hours. The compound (1 μM, 24 h) also leads to upregulation of Ac-α-tubulin, comparable to Vorinostat's effect, and degrades class IIb HDACs via the ubiquitin-proteasome system. Additionally, it induces degradation of new substrates in MM.1S cells via CRBN independent of HDAC binding (1-5 μM, 6-24 h). Furthermore, PROTAC HDAC degrader-2 (10 μM, 48 h) significantly extends the G1 phase in MM.1S cells and does not affect LC3-I and LC3-II levels (1-5 μM, 24 h). Moreover, in MDA-MB-231 cells, it markedly inhibits cell migration (1-5 μM, 24 h).