2. Academic Validation
  3. Design and synthesis of HDAC inhibitors to enhance the therapeutic effect of diffuse large B-cell lymphoma by improving metabolic stability and pharmacokinetic characteristics

Design and synthesis of HDAC inhibitors to enhance the therapeutic effect of diffuse large B-cell lymphoma by improving metabolic stability and pharmacokinetic characteristics

  • Eur J Med Chem. 2022 Feb 5;229:114049. doi: 10.1016/j.ejmech.2021.114049.
Hao Cui 1,  Qianqian Hong 1,  Ran Wei 1,  Hongmei Li 1,  Chunyang Wan 1,  Xin Chen 2,  Shuang Zhao 1,  Haizhi Bu 3,  Bingxu Zhang 3,  Dexiao Yang 3,  Tao Lu 4,  Yadong Chen 5,  Yong Zhu 6
Affiliations

Affiliations

  • 1 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 2 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China.
  • 3 3D BioOptima Co. Ltd., Suzhou Ace Park, 1338 Wuzhong Blvd, Wuzhong District, Suzhou, 215104, PR China.
  • 4 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: lutao@cpu.edu.cn.
  • 5 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: ydchen@cpu.edu.cn.
  • 6 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: zhuyong@cpu.edu.cn.
PMID: 34954594 DOI: 10.1016/j.ejmech.2021.114049
Abstract

Histone deacetylases (HDAC) are clinically validated and attractive epigenetic drug targets for human cancers. Several HDAC inhibitors have been approved for Cancer treatment to date, however, clinical applications have been limited due to the poor pharmacokinetics, bioavailability, selectivity of the HDAC inhibitors and most of them need to be combined with other drugs to achieve better results. Here, we describe our efforts toward the discovery of a novel series of lactam-based derivatives as selective HDAC inhibitors. Intensive structural modifications lead to the identification of compound 24g as the most active Class I HDAC Inhibitor, along with satisfactory metabolic stability in vitro (t1/2, human = 797 min) and the desirable oral bioavailability (F = 92%). More importantly, compound 24g showed good antitumor efficacy in a TMD-8 xenograft model (TGI = 77%) without obvious toxicity. These results indicated that Class I HDAC Inhibitor could be potentially used to treat certain diffuse large B-cell lymphoma therapeutics.

Keywords

Bioavailability; Diffuse large B-Cell lymphoma; HDAC; Inhibitors; Metabolic stability.

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