HDAC6 inhibitors(Zhengzhou University)

Phosphoinositide 3-kinases (PI3Ks) and histone deacetylase 6 (HDAC6) have been widely studied as promising therapeutic targets in cancer. Both play key roles in maintaining cellular homeostasis, and their dysregulation is closely linked to oncogenesis. Consequently, several dual PI3K/HDAC6 inhibitors have been developed as potential anticancer agents. This review explores the cellular and molecular functions of PI3K and HDAC6, their involvement in cancer progression, and the structural and pharmacological properties of dual-targeting inhibitors. Additionally, we discuss future perspectives for designing clinically effective dual PI3K/HDAC6 inhibitors.

Selective histone deacetylase 6 inhibitors show distinctive advantages for cancer treatment. In this paper, phenylhydroxamic acid group, a key pharmacophore of histone deacetylase 6 inhibitor, is introduced on common active pyrazolo[1,5‐a]pyrimidine scaffold. Among all thirteen analogs, N ‐hydroxy‐4‐(((7‐(4‐methoxyphenyl)pyrazolo[1,5‐a]pyrimidin‐5‐yl)amino)methyl)benzamide ( 8e ) emerged as the most potent compound. Enzymatic assay showed that it potently inhibited histone deacetylase 6 with IC 50 of 3.84 nM, and demonstrated a 412‐fold selectivity relative to the inhibition of histone deacetylase 1. In antiproliferative study, 8e also exhibited good antiproliferative activity against HL‐60 and SK‐MEL‐2 cell lines with IC 50 of 0.2 and 0.35 nM, respectively. Molecular docking simulation indicated the binding site of histone deacetylase 6 could well accommodate pyrazolo[1,5‐a]pyrimidine core, yielding a variety of interactions.