Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties

Bioorg Med Chem Lett. 2013 Aug 1;23(15):4374-80. doi: 10.1016/j.bmcl.2013.05.075. Epub 2013 May 31.

Abstract

The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC₅₀ ≤ 50 nM versus CK1δ. The two lead compounds have ≤100 nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • Casein Kinase 1 epsilon / antagonists & inhibitors*
  • Casein Kinase 1 epsilon / metabolism
  • Casein Kinase Idelta / antagonists & inhibitors*
  • Casein Kinase Idelta / metabolism
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Survival
  • Half-Life
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Purines / chemistry
  • Purines / pharmacokinetics
  • Purines / therapeutic use
  • Rats
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Purines
  • SR-2890
  • SR-3029
  • Casein Kinase 1 epsilon
  • Casein Kinase Idelta
  • purine