Identification of triazolyl KAT6 inhibitors via a templated fragment approach

Bioorg Med Chem Lett. 2024 Nov 15:113:129948. doi: 10.1016/j.bmcl.2024.129948. Epub 2024 Sep 3.

Abstract

KAT6, a histone acetyltransferase from the MYST family, has emerged as an attractive oncology target due to its role in regulating genes that control cell cycle progression and cellular senescence. Amplification of the KAT6A gene has been seen among patients with worse clinical outcome in ER+ breast cancers. Although multiple inhibitors have been reported, no KAT6 inhibitors have been approved to date. Here, we report the fragment-based discovery of a series of N-(1-phenyl-1H-1,2,3-triazol-4-yl)benzenesulfonamide KAT6 inhibitors and early hit-to-lead efforts to improve the KAT6 potency.

Keywords: Breast cancer; FBDD; Histone acetyltransferase inhibitor; KAT6.

MeSH terms

  • Benzenesulfonamides
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Histone Acetyltransferases* / antagonists & inhibitors
  • Histone Acetyltransferases* / metabolism
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Triazoles* / chemical synthesis
  • Triazoles* / chemistry
  • Triazoles* / pharmacology

Substances

  • Histone Acetyltransferases
  • Triazoles
  • KAT6A protein, human
  • Enzyme Inhibitors
  • Sulfonamides
  • Benzenesulfonamides