2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of HDAC Degraders with CRBN E3 Ligase Ligands

Design, Synthesis, and Biological Evaluation of HDAC Degraders with CRBN E3 Ligase Ligands

  • Molecules. 2021 Nov 29;26(23):7241. doi: 10.3390/molecules26237241.
Yingxin Lu 1,  Danwen Sun 2,  Donghuai Xiao 1,  Yingying Shao 2,  Mingbo Su 2,  Yubo Zhou 2,  Jia Li 2,  Shulei Zhu 1,  Wei Lu 1
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
  • 2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China.
PMID: 34885822 DOI: 10.3390/molecules26237241
Abstract

Histone deacetylases (HDACs) play important roles in cell growth, cell differentiation, cell Apoptosis, and many other cellular processes. The inhibition of different classes of HDACs has been shown to be closely related to the therapy of cancers and Other Diseases. In this study, a series of novel CRBN-recruiting HDAC PROTACs were designed and synthesized by linking hydroxamic acid and benzamide with lenalidomide, pomalidomide, and CC-220 through linkers of different lengths and types. One of these PROTACs, denoted 21a, with a new benzyl alcohol linker, exhibited comparably excellent HDAC inhibition activity on different HDAC classes, acceptable degradative activity, and even better in vitro anti-proliferative activities on the MM.1S cell line compared with SAHA. Moreover, we report for the first time the benzyl alcohol linker, which could also offer the potential to be used to develop more types of potent PROTACs for targeting more proteins of interest (POI).

Keywords

CRBN ligands; HDAC degraders; benzyl alcohol linkage; proteins of interest.

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