1328624-10-7Relevant articles and documents
Synthesis and biological evaluation of pyrimidine-based dual inhibitors of human epidermal growth factor receptor 1 (HER-1) and HER-2 tyrosine kinases
Cha, Mi Young,Lee, Kwang-Ok,Kang, Seok-Jong,Jung, Young Hee,Song, Ji Yeon,Choi, Kyung Jin,Byun, Joo Yun,Lee, Han-Jae,Lee, Gwan Sun,Park, Seung Bum,Kim, Maeng Sup
, p. 2846 - 2857 (2012/06/01)
A novel series of N4-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine- 4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases. In contrast to the currently approved HER-2-targeted agent (lapatinib, 1), our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance. The selected compound (19a) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine kinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types: lapatinib-sensitive cell lines (SK-Br3, MDA-MB-175, and N87) and lapatinib-resistant cell lines (MDA-MB-453, H1781, and H1975). The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors, especially HER-2-positive breast/gastric cancer and HER-2-mutated lung cancer.