Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma

Bioorg Med Chem Lett. 2018 Sep 15;28(17):2985-2992. doi: 10.1016/j.bmcl.2018.06.029. Epub 2018 Jun 18.

Abstract

A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.

Keywords: CTCL; HDAC inhibitors; Mycosis fungoides; Squaramide; Topical.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase 1 / antagonists & inhibitors*
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / antagonists & inhibitors*
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Lymphoma, T-Cell, Cutaneous / drug therapy*
  • Lymphoma, T-Cell, Cutaneous / metabolism
  • Lymphoma, T-Cell, Cutaneous / pathology
  • Models, Molecular
  • Molecular Structure
  • Quinine / analogs & derivatives*
  • Quinine / chemical synthesis
  • Quinine / chemistry
  • Quinine / pharmacology
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Solubility
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • squaramide
  • Quinine
  • Histone Deacetylase 1
  • Histone Deacetylase 2