Replacement of the hydroxamic acid group in the selective HDAC8 inhibitor PCI-34051

Bioorg Med Chem Lett. 2024 Aug 1:108:129810. doi: 10.1016/j.bmcl.2024.129810. Epub 2024 May 22.

Abstract

PCI-34051 is a valuable tool to interrogate the therapeutic effects of selective inhibition of HDAC8. However, it has not advanced to clinical trials, perhaps due to poor PK or off-target effects. We hypothesized that the presence of a hydroxamic acid (HA) group in PCI-34051 contributed to its lack of advancement. Therefore, we replaced the HA in the PCI-34051 scaffold with a series of moieties that have the potential to bind to Zn and evaluated their activity in a HDAC8 assay. Surprisingly, none of the replacements effectively mimicked the HA, and analogs lost significant potency. Evaluation of the analogs' affinity to Zn indicated that none had affinity for Zn within the same range as the HA. These studies point to the difficulty in the application of bioisosteric replacements for Zn binding motifs.

Keywords: Histone deacetylase 8; Hydroxamic acid; Isosteric replacement; PCI-34051.

MeSH terms

  • Dose-Response Relationship, Drug
  • Histone Deacetylase Inhibitors* / chemical synthesis
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylase Inhibitors* / pharmacology
  • Histone Deacetylases* / metabolism
  • Humans
  • Hydroxamic Acids* / chemical synthesis
  • Hydroxamic Acids* / chemistry
  • Hydroxamic Acids* / pharmacology
  • Indoles
  • Molecular Structure
  • Repressor Proteins* / antagonists & inhibitors
  • Repressor Proteins* / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Zinc / chemistry
  • Zinc / pharmacology

Substances

  • Histone Deacetylases
  • Hydroxamic Acids
  • HDAC8 protein, human
  • Histone Deacetylase Inhibitors
  • Repressor Proteins
  • PCI 34051
  • Zinc
  • Sulfonamides
  • Indoles