HDSI-18

In stark contrast to other HDAC isoforms, deletion or inhibition of HDAC6 suppresses cell proliferation without lethality or defective phenotypes, thereby establishing HDAC6 as a compelling anti-cancer target. In pursuit of safe and effective anti-cancer chemotherapy, we preformed three-round structural optimization and developed several potent HDAC6-selective inhibitors. Among these, HDSI-18 exhibited remarkable inhibitory activity (IC₅₀ = 1.6 nM) and exceptional isoform selectivity (over 975-fold) against HDAC6. Further biological evaluations highlighted the promising properties of HDSI-18 in terms of anti-proliferative activity, mitochondrial depolarization, caspase-3 activation, apoptosis induction and druggability (both in vivo and in vitro). This study demonstrated a paradigm for the rational structural optimization of HDAC6 selective inhibitors, which may serve as a beacon for the development of more promiscuous compounds.