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

  • Bioorg Med Chem Lett. 2008 Aug 15;18(16):4615-9. doi: 10.1016/j.bmcl.2008.07.020.
Guozhang Xu  1 ,  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
Affiliations
  • 1. Johnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry, 8 Clarke Drive, Cranbury, NJ 08512, USA. [email protected]
PMID: 18653333 DOI: 10.1016/j.bmcl.2008.07.020
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 (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.