Xu Guozhang, Abad Marta C, Connolly Peter J, Neeper Michael P, Struble Geoffrey T, Springer Barry A, Emanuel Stuart L, Pandey Niranjan, Gruninger Robert H, Adams Mary, Moreno-Mazza Sandra, Fuentes-Pesquera Angel R, Middleton Steven A
Johnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry, 8 Clarke Drive, Cranbury, NJ 08512, USA.
Bioorg Med Chem Lett. 2008 Aug 15;18(16):4615-9. doi: 10.1016/j.bmcl.2008.07.020. Epub 2008 Jul 10.
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.
使用概念引导设计方法，一类新型的4-氨基-6-芳基氨基嘧啶-5-甲醛腙被鉴定为有效的双ErbB-2/EGFR激酶抑制剂。这些化合物在体外抑制ErbB-2过表达的人肿瘤细胞系（BT474、N87和SK-BR-3）的生长。化合物15成为关键先导物，显示出显著抑制SK-BR-3细胞中生长因子诱导的受体磷酸化的能力（IC(50)=54 nM）以及体外细胞增殖能力（BT474、N87和SK-BR-3的IC(50)分别为14、58和58 nM）。确定了EGFR与一种类似物（17）的X射线共晶体结构，并验证了我们的设计原理。
