Aminopyridine-Based c-Jun N-Terminal Kinase Inhibitors with Cellular Activity and Minimal Cross-Kinase Activity
Citations Over TimeTop 10% of 2006 papers
Abstract
The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases.
Related Papers
- → The Role of MAP Kinases in Trauma and Ischemia–Reperfusion(2004)27 cited
- → The Role of MAP Kinases in Trauma and Ischemia–Reperfusion(2004)11 cited
- → Intracellular Signal Cascade in CD4+T-Lymphocyte Migration Stimulated by Interferon-γ-Inducible Protein-10(2005)7 cited
- → Effect of Angiotensin III on ERK1/2 and p38 mitogen activated protein (MAP) kinases in Wistar rat VSMCs(2015)
- → Phosphorylation of MAP kinases by MAP/ERK kinases involves multiple regions of MAP kinases.(1999)