RESUMO
The importance of transforming growth factor beta-activated kinase 1 (TAK1) to cell survival has been demonstrated in many studies. TAK1 regulates signalling cascades, the NF-κB pathway and the mitogen-activated protein kinase (MAPK) pathway. TAK1 inhibitors can induce the apoptosis of cancerous cells, and irreversible inhibitors such as (5Z)-7-oxozeaenol are highly potent. However, they can react non-specifically with cysteine residues in proteins, which may have serious adverse effects. Reversible covalent inhibitors have been suggested as alternatives. We synthesised imidazopyridine derivatives as novel TAK1 inhibitors, which have 2-cyanoacrylamide moiety that can form reversible covalent bonding. A derivative with 2-cyano-3-(6-methylpyridin-2-yl)acrylamide (13h) exhibited potent TAK1 inhibitory activity with an IC50 of 27 nM. It showed a reversible reaction with ß-mercaptoethanol, which supports its potential as a reversible covalent inhibitor.
Assuntos
Acrilamida/química , Imidazóis/síntese química , MAP Quinase Quinase Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Piridinas/síntese química , Sítios de Ligação , Humanos , Imidazóis/metabolismo , Mercaptoetanol/química , Modelos Moleculares , NF-kappa B/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Piridinas/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Fator de Transcrição RelA , Zearalenona/análogos & derivados , Zearalenona/químicaRESUMO
Transforming growth factor-ß activated kinase-1 (TAK1) is a potential therapeutic target for cancers and inflammatory diseases. We synthesized a series of novel imidazopyrazine derivatives, which were found to exhibit potent inhibitory effect against TAK1. Compound 22a, which possesses a good pharmacokinetic profile, showed excellent in vitro kinase activity and significant in vivo efficacy in mice xenografted with SW620, a KRAS-dependent colon cancer cell line.
Assuntos
MAP Quinase Quinase Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirazinas/uso terapêutico , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Xenoenxertos , Humanos , Inflamação/tratamento farmacológico , Camundongos , Neoplasias/tratamento farmacológico , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazinas/farmacologiaRESUMO
A novel series of N(4)-(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.
