2. Academic Validation
  3. Serendipitous discovery of Class I HDAC inhibitors from rational design of molecular glue degraders targeting HDAC

Serendipitous discovery of Class I HDAC inhibitors from rational design of molecular glue degraders targeting HDAC

  • Eur J Med Chem. 2023 Nov 19:263:115926. doi: 10.1016/j.ejmech.2023.115926.
Di Chen 1,  Shuxian Lin 2,  Ziwei Zeng 1,  Jianxiong An 1,  Wanli Yan 1,  Zhicheng Gu 1,  Lei Chen 1,  Bin He 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China.
  • 2 State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China; Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
  • 3 State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China. Electronic address: binhe@gmc.edu.cn.
PMID: 37995564 DOI: 10.1016/j.ejmech.2023.115926
Abstract

Zinc-dependent histone deacetylases (HDACs) play an essential role as epigenetic regulators and are becoming increasingly important drug targets for the treatment of Cancer. Although five HDAC inhibitors have been approved for treating several cancers, only one of them is a Class I HDAC Inhibitor, which may have advantages over pan-HDAC inhibitors due to the various side effects associated with the latter. On the other hand, the emerging strategy of molecular glue degraders offers a unique advantage for targeting therapeutic proteins. In this study, we synthesized a series of candidate compounds based on the molecule glue, pomalidomide, using a "merger principle", initially aiming to obtain molecular glue degraders that can target HDAC degradation. However, we serendipitously discovered that compounds 2f and 3f may be potent Class I HDAC selective inhibitors. After further evaluation, we found that compounds 2f and 3f exhibit selective inhibitory effects on Class I HDAC in Cancer cells. Moreover, they showed the robust antiproliferative activities against various hematological tumor cells, comparable to that of the approved Class I HDAC Inhibitor, Chidamide. These results suggest that pomalidomide-derivatized compounds have promising potential as Class I HDAC inhibitors with therapeutic applications in Cancer treatment.

Keywords

Anticancer; Class; Degrader; HDAC; Inhibitor; Pomaildomide.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157215
    HDAC Inhibitor