4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors

Guozhang Xu, Marta C. Abad, Peter J. Connolly, Michael P. Neeper, Geoffrey T. Struble, Barry A. Springer, Stuart L. Emanuel, Niranjan Pandey, Robert H. Gruninger, Mary Adams, Sandra Moreno-Mazza, Angel R. Fuentes-Pesquera, Steven A. Middleton

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC50 = 54 nM) and cellular proliferation in vitro (IC50 = 14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.

Original languageEnglish (US)
Pages (from-to)4615-4619
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number16
StatePublished - Aug 15 2008
Externally publishedYes


  • Bioisostere
  • EGFR
  • ErbB-2
  • Hydrazones
  • Quinazoline
  • Receptor tyrosine kinase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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