The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington's Disease

J Med Chem. 2022 Dec 22;65(24):15993-16032. doi: 10.1021/acs.jmedchem.2c00799. Epub 2022 Dec 9.


Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). The new insights into HD's cellular and molecular pathways have led to the identification of numerous potent small-molecule therapeutics for HD therapy. The field of HD-targeting small-molecule therapeutics is accelerating, and the approval of these therapeutics to combat HD may be expected in the near future. For instance, preclinical candidates such as naphthyridine-azaquinolone, AN1, AN2, CHDI-00484077, PRE084, EVP4593, and LOC14 have shown promise for further optimization to enter into HD clinical trials. This perspective aims to summarize the advent of small-molecule therapeutics at various stages of clinical development for HD therapy, emphasizing their structure and design, therapeutic effects, and specific mechanisms of action. Further, we have highlighted the key drivers involved in HD pathogenesis to provide insights into the basic principle for designing promising anti-HD therapeutic leads.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Humans
  • Huntingtin Protein / genetics
  • Huntington Disease* / drug therapy
  • Huntington Disease* / genetics


  • Huntingtin Protein
  • 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
  • LOC14