Advances in dual-targeting inhibitors of HDAC6 for cancer treatment

Eur J Med Chem. 2024 Sep 5:275:116571. doi: 10.1016/j.ejmech.2024.116571. Epub 2024 Jun 6.

Abstract

Histone Deacetylase 6 (HDAC6) is an essential regulator of histone acetylation processes, exerting influence on a multitude of cellular functions such as cell motility, endocytosis, autophagy, apoptosis, and protein trafficking through its deacetylation activity. The significant implications of HDAC6 in diseases such as cancer, neurodegenerative disorders, and immune disorders have motivated extensive investigation into the development of specific inhibitors targeting this enzyme for therapeutic purposes. Single targeting drugs carry the risk of inducing drug resistance, thus prompting exploration of dual targeting therapy which offers the potential to impact multiple signaling pathways simultaneously, thereby lowering the likelihood of resistance development. While pharmacological studies have exhibited promise in combined therapy involving HDAC6, challenges related to potential drug interactions exist. In response to these challenges, researchers are investigating HDAC6 hybrid molecules which enable the concomitant targeting of HDAC6 and other key proteins, thus enhancing treatment efficacy while mitigating side effects and reducing the risk of resistance compared to traditional combination therapies. The published design strategies for dual targeting inhibitors of HDAC6 are summarized and discussed in this review. This will provide some valuable insights into more novel HDAC6 dual targeting inhibitors to meet the urgent need for innovative therapies in oncology and other related fields.

Keywords: Dual-targeting inhibitors; HDAC6; Hybrid molecules.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Histone Deacetylase 6* / antagonists & inhibitors
  • Histone Deacetylase 6* / metabolism
  • Histone Deacetylase Inhibitors* / chemical synthesis
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylase Inhibitors* / pharmacology
  • Humans
  • Molecular Structure
  • Neoplasms* / drug therapy

Substances

  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors
  • HDAC6 protein, human
  • Antineoplastic Agents