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

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 (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=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.

[1]  K. Lackey,et al.  Discovery and biological evaluation of potent dual ErbB-2/EGFR tyrosine kinase inhibitors: 6-thiazolylquinazolines. , 2003, Bioorganic & medicinal chemistry letters.

[2]  W. Gullick,et al.  Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. , 1991, British medical bulletin.

[3]  D Tripathy,et al.  Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  N. Normanno,et al.  Epidermal growth factor-related peptides and their receptors in human malignancies. , 1995, Critical reviews in oncology/hematology.

[5]  Monilola A. Olayioye,et al.  The ErbB signaling network: receptor heterodimerization in development and cancer , 2000, The EMBO journal.

[6]  A. Gomtsyan,et al.  Design, Synthesis, and Structure−Activity Relationship of 6-Alkynylpyrimidines as Potent Adenosine Kinase Inhibitors , 2002 .

[7]  J. Woodburn,et al.  The epidermal growth factor receptor and its inhibition in cancer therapy. , 1999, Pharmacology & therapeutics.

[8]  Stu Borman.  HOPES RIDE ON DRUG CANDIDATES: Researchers reveal potential new medicines for thrombosis, anxiety, diabetes, and cancer , 2005 .

[9]  Mary Adams,et al.  Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases. , 2008, Bioorganic & medicinal chemistry letters.

[10]  J. Tokarski,et al.  New dual inhibitors of EGFR and HER2 protein tyrosine kinases. , 2005, Bioorganic & medicinal chemistry letters.

[11]  Krystal J Alligood,et al.  A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib) , 2004, Cancer Research.

[12]  H. Waksal.  Role of an Anti-epidermal Growth Factor Receptor in Treating Cancer , 2004, Cancer and Metastasis Reviews.

[13]  K. Lackey,et al.  The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. , 2001, Molecular cancer therapeutics.