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

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

  • J Med Chem. 2026 Mar 12;69(5):6111-6137. doi: 10.1021/acs.jmedchem.5c03600.
Li-Yan Zhou 1,  Ya-Ling Li 1,  Jing-Dong Zhang 1,  Xin-Yu Zhang 1,  Mei-Ling He 1,  Ting Shi 1,  Zi-Qiang Chen 1,  You-Cai Xiao 1,  Fen-Er Chen 1 2 3 4
Affiliations

Affiliations

  • 1 Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 2 Institute of Flow Chemistry and Engineering, School of Chemistry and Materials, Jiangxi Normal University, Nanchang 330022, China.
  • 3 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
  • 4 Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
PMID: 41733326 DOI: 10.1021/acs.jmedchem.5c03600
Abstract

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.

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