Harnessing Unique Boron Chemistry to Develop a New Class of Non-hydroxamate HDAC Inhibitors with Validated In Vivo Efficacy

Boron's dynamic covalent reactivity and flexible coordination offer medicinal promise yet remain underexplored in metalloenzyme pharmacophore design. In this study, a series of novel boronic acid-based HDAC inhibitors were designed and further optimized via amide-to-imidazole cyclization to enhance potency and pharmacokinetics. Among these compounds, <b>Z16</b> showed potent HDAC inhibition (IC₅₀ 37.73 nM) and broad-spectrum antiproliferative activity, with IC₅₀ values of 0.02-0.10 μM in various cell lines. In vitro and in vivo pharmacokinetic evaluation revealed that <b>Z16</b> possesses a set of characteristics─including species-dependent metabolic stability, extensive tissue distribution, and high absolute bioavailability following intraperitoneal administration (i.p.). <b>Z16</b> also showed comparable antitumor activity in an HCT116 xenograft model without causing significant loss of body weight or toxicity. These findings establish <b>Z16</b> as a promising lead for nonhydroxamate HDAC inhibitors and highlight boronic acid's potential as a metalloenzyme-targeted pharmacophore.