A three-step protocol for lead optimization: quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitors

Bioorg Med Chem Lett. 2012 Jan 1;22(1):65-70. doi: 10.1016/j.bmcl.2011.11.074. Epub 2011 Nov 23.

Abstract

A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap observed between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compound 28 was identified with single digit binding activity (IC(50)=8 nM) and good cellular activity (EC(50)=310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Animals
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Mice
  • Models, Chemical
  • Molecular Conformation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases