The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase

Bioorg Med Chem Lett. 2009 Oct 15;19(20):5950-3. doi: 10.1016/j.bmcl.2009.08.038. Epub 2009 Aug 13.

Abstract

We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Diamines / chemical synthesis
  • Diamines / chemistry*
  • Diamines / pharmacology
  • Drug Discovery
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Morpholines / chemical synthesis
  • Morpholines / chemistry*
  • Morpholines / pharmacology
  • Multiprotein Complexes
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry*
  • Protein Kinases / metabolism
  • Proteins
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism

Substances

  • Antineoplastic Agents
  • CRTC2 protein, human
  • Diamines
  • Morpholines
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Proteins
  • Pyrimidines
  • Transcription Factors
  • Ku 0063794
  • Protein Kinases
  • MTOR protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases