Chiral kinase inhibitors.

Medicinal Chemistry


Small molecule kinase inhibitors are important tools for studying cellular signaling pathways, phenotypes and are, occasionally, useful clinical agents. With stereochemistry pervasive throughout the molecules of life it is no surprise that a single stereocenter can bestow a ligand with distinct binding affinities to various protein targets. While the majority of small molecule kinase inhibitors reported to date are achiral, a number of asymmetric compounds show great utility as tools for probing kinase-associated biomolecular events as well as promising therapeutic leads. The mechanism by which chirality is introduced varies but includes screening of chiral libraries, incorporation of chiral centers during optimization efforts and the rational installation of a chiral moiety as guided by structural and modeling efforts. Here we discuss several advanced chiral small molecule kinase inhibitors where stereochemistry plays an important role in terms of potency and selectivity.


Jiang, Jian-Kang; Shen, Min; Thomas, Craig; Boxer, Mathew B;


  • Animals
  • Binding Sites/ drug effects
  • Humans
  • Janus Kinase 3/ chemistry
  • Janus Kinase 3/ metabolism
  • MAP Kinase Kinase Kinase 3/ chemistry
  • MAP Kinase Kinase Kinase 3/ metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 14/ chemistry
  • Mitogen-Activated Protein Kinase 14/ metabolism
  • Models, Molecular
  • Neoplasms/ drug therapy
  • Protein Binding/ drug effects
  • Protein Kinase Inhibitors/ chemistry
  • Protein Kinase Inhibitors/ pharmacology
  • Protein Kinase Inhibitors/ therapeutic use
  • Proto-Oncogene Proteins c-akt/ chemistry
  • Proto-Oncogene Proteins c-akt/ metabolism
  • Rats
  • Receptor, trkA/ chemistry
  • Receptor, trkA/ metabolism
  • Signal Transduction/ drug effects
  • Small Molecule Libraries/ chemistry
  • Small Molecule Libraries/ pharmacology
  • Small Molecule Libraries/ therapeutic use
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

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