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4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors. 2008
Guozhang Xu, and
Marta C Abad, and
Peter J Connolly, and
Michael P Neeper, and
Geoffrey T Struble, and
Barry A Springer, and
Stuart L Emanuel, and
Niranjan Pandey, and
Robert H Gruninger, and
Mary Adams, and
Sandra Moreno-Mazza, and
Angel R Fuentes-Pesquera, and
Steven A Middleton
Johnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry, 8 Clarke Drive, Cranbury, NJ 08512, USA. gxu4@prdus.jnj.com
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.
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