Substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as multi-targeted inhibitors of insulin-like growth factor-1 receptor (IGF1R) and members of ErbB-family receptor kinases

  • Bioorg Med Chem Lett. 2010 Oct 15;20(20):6067-71. doi: 10.1016/j.bmcl.2010.08.052.
Gary T Wang  1 ,  Robert A Mantei ,  Robert D Hubbard ,  Julie L Wilsbacher ,  Qian Zhang ,  Lora Tucker ,  Xiaoming Hu ,  Peter Kovar ,  Eric F Johnson ,  Donald J Osterling ,  Jennifer Bouska ,  Jieyi Wang ,  Steven K Davidsen ,  Randy L Bell ,  George S Sheppard
Affiliations
  • 1. Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. [email protected]
PMID: 20817523 DOI: 10.1016/j.bmcl.2010.08.052
Abstract

This Letter describes the lead discovery, optimization, and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR, and ErbB2. The leading compound 11 showed an IGF1R IC(50) of 12 nM, an EGFR (L858R) IC(50) of 31 nM, and an ErbB2 IC(50) of 11 nM, potent activity in cellular functional and anti-proliferation assays, as well as activity in an in vivo pharmacodynamic assay.