Abstract A248: Substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as multitargeted inhibitors targeting insulin-like growth factor-1 receptor (IGF1R) and members of ErbB-family receptor tyrosine kinases

Insulin‐like growth factor‐1 receptor (IGF1R) and members of ErbB family (eg. EGFR, ErbB2) are receptor tyrosine kianses that play significant roles in cancer and have been pursued as drug targets for cancer therapy. There is substantial evidence for the existence of reciprocal cross‐talk between IGF1R axis and ErbB axis of cellular signaling. Acquired resistance to EGFR inhibitors gefitinib and erlotinib or ErbB2 inhibitor trastuzumab has been linked to activation of IGF1R signaling through induced overexpression of IGF1R or loss of IGF binding‐ proteins. Additionally, synergy between IGF1R inhibition and ErbB inhibition has been demonstrated in cancer cell growth inhibition and in xenograft models. Thus, molecules targeting both IGF1R and ErbB‐family might have superior anti‐tumor efficacy. This poster describes the lead discovery, optimization and biological characterization of a series of substituted 4‐amino‐1 H ‐pyrazolo[3,4‐ d ]pyrimidines as potent inhibitors of IGF1R, EGFR and ErbB2. The leading compound, A‐923573, showed IGF1R IC 50 of 12 nM, EGFR (L858R) IC 50 of 31 nM and ErbB2 IC 50 of 11 nM, potent activity in cellular functional assays and anti‐proliferation assays, as well as in an in vivo pharmacodynamic assay. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A248.