Author/Authors :
Guozhang Xu، نويسنده , , Marta C. Abad، نويسنده , , Peter J. Connolly، نويسنده , , Michael P. Neeper، نويسنده , , Geoffrey T. Struble، نويسنده , , Barry A. Springer، نويسنده , , Stuart L. Emanuel، نويسنده , , Niranjan Pandey، نويسنده , , Robert H. Gruninger، نويسنده , , MARY ADAMS، نويسنده , , Sandra Moreno-Mazza، نويسنده , , Angel R. Fuentes-Pesquera، نويسنده , , Steven A. Middleton، نويسنده ,
Abstract :
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.
Keywords :
hydrazones , EGFR , ErbB-2 , Bioisostere , Receptor tyrosine kinase , Quinazoline
