2. Academic Validation
  3. The application of PROTAC in HDAC

The application of PROTAC in HDAC

  • Eur J Med Chem. 2023 Nov 15:260:115746. doi: 10.1016/j.ejmech.2023.115746.
Shaoting Chen 1,  Yuxiang Zheng 1,  Benji Liang 1,  Yudong Yin 1,  Jian Yao 1,  Quande Wang 2,  Yanghan Liu 3,  Nouri Neamati 4
Affiliations

Affiliations

  • 1 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China.
  • 2 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: quande_wang@163.com.
  • 3 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: lyh4291006@163.com.
  • 4 Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States. Electronic address: neamati@umich.edu.
PMID: 37607440 DOI: 10.1016/j.ejmech.2023.115746
Abstract

Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone deacetylase (HDAC)-PROTAC has been widely developed since the first report of its ability to induce the degradation of SIRT2 in 2017. To date, ten of the eighteen HDACs (HDACs 1-8, HDAC10, and SIRT2) have been successfully targeted and degraded by HDAC-PROTACs. HDAC-PROTACs surpass traditional HDAC inhibitors in many aspects, such as higher selectivity, more potent antiproliferative activity, and the ability to disrupt the enzyme-independent functions of a multifunctional protein and overcome drug resistance. Rationally designing HDAC-PROTACs is a main challenge in development because slight variations in chemical structure can lead to drastic effects on the efficiency and selectivity of the degradation. In the future, HDAC-PROTACs can potentially be involved in clinical research with the support of the increased amount of in vivo data, pharmacokinetic evaluation, and pharmacological studies.

Keywords

Histone deacetylases; PROTAC; Protein degradation; Proteolysis-targeting chimera; Sirtuins.

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