2,4-Diarylamino-pyrimidines as kinase inhibitors co-targeting IGF1R and EGFR(L⁸⁵⁸R/T⁷⁹⁰M)

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4277-81. doi: 10.1016/j.bmcl.2015.07.089. Epub 2015 Jul 30.


IGF1R amplification was recently implied to be related to the secondary acquired resistance against the 2nd or 3rd generation EGFR inhibitor therapies. We have successfully identified a series of 2,4-diarylamino-pyrimidines as new IGF1R/EGFR(L858R/T790M) co-targeting agents. One of the most promising compounds 8g potently inhibits both kinases with low nanomolar IC50 values, but is significantly less potent in inhibiting the wild type EGFR. The compound also displays a good kinase selectivity profile against a panel of 468 kinases. Moreover, 8g strongly suppresses the proliferation of CO-1686-resistant H1975-IGF1R cancer cells, suggesting its promising potential as a new lead compound for future anticancer drug discovery.

Keywords: Dual inhibitor; EGFR; IGF1R; NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / antagonists & inhibitors*
  • Receptors, Somatomedin / metabolism
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • IGF1R protein, human
  • Protein Kinase Inhibitors
  • Receptors, Somatomedin
  • EGFR protein, human
  • ErbB Receptors
  • Receptor, IGF Type 1