Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors

Bioorg Med Chem Lett. 2012 Jul 1;22(13):4377-85. doi: 10.1016/j.bmcl.2012.04.131. Epub 2012 May 5.

Abstract

Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemistry
  • Adenine / pharmacokinetics
  • Adenine / toxicity
  • Administration, Oral
  • Animals
  • Apoptosis / drug effects
  • Binding Sites
  • Crystallography, X-Ray
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • HCT116 Cells
  • Humans
  • M Phase Cell Cycle Checkpoints / drug effects
  • Mice
  • Molecular Conformation
  • Morpholines / chemistry*
  • Morpholines / pharmacokinetics
  • Morpholines / toxicity
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / toxicity
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Purines / chemistry*
  • Structure-Activity Relationship

Substances

  • MPI-0479605
  • Morpholines
  • Protein Kinase Inhibitors
  • Purines
  • Ttk protein, mouse
  • Protein Serine-Threonine Kinases
  • Adenine
  • purine