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

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, Z16 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 Z16 possesses a set of characteristics─including species-dependent metabolic stability, extensive tissue distribution, and high absolute bioavailability following intraperitoneal administration (i.p.). Z16 also showed comparable antitumor activity in an HCT116 xenograft model without causing significant loss of body weight or toxicity. These findings establish Z16 as a promising lead for nonhydroxamate HDAC inhibitors and highlight boronic acid's potential as a metalloenzyme-targeted pharmacophore.