P38α inhibitor,highly potent and selective
CAS：209410-46-8
分子式：C19H9Cl2F2N3OS
分子量：436.27
纯度：98%
存储：Store at -20°C

Background:

VX-745 is a first-generation inhibitor of p38αMAPK with IC50 value of 1.0 μM when tested with Werner syndrome dermal fibroblasts [1].

Mammalian mitogen-activated protein (MAP) kinases are serine /threonine kinases and have 4 subfamilies: ERK, JNK, MAPKp38 and ERK5. MAPK pathway plays a pivotal role in transmitting signals from cell membrane to nucleus and also participates in many intracellular signaling pathways that control a wide spectrum of cellular processes (growth, differentiation, stress responses, cancer progression) [2]. MAPKp38 is originally isolated from lipopolysaccharide-stimulated monocytes. And according to the distribution in tissue, regulation of kinase activation and subsequent phosphorylation of downstream substrates, it is divided into four isoforms p38alpha, p38beta, p38gamma and p38delta [3].

VX-745 is an exquisite kinase selectively inhibit p38αMAPK and is regarded as an anti-inflammatory candidate. When tested with PBMCs or whole blood, VX-745 treatment could inhibit the secretion of IL-1β and TNF-α in vitro [4]. In human dermal fibroblast cells, VX-745 treatment blocked p38 signaling to rescue the aging phenotype in Werner syndrome [5].

参考文献:
[1].  Bagley, M.C., et al., Microwave-assisted Ullmann C-S bond formation: synthesis of the P38alpha MAPK clinical candidate VX-745. J Org Chem, 2009. 74(21): p. 8336-42.
[2].  Dent, P., et al., MAPK pathways in radiation responses. Oncogene, 2003. 22(37): p. 5885-96.
[3].  Dominguez, C., D.A. Powers, and N. Tamayo, p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Devel, 2005. 8(4): p. 421-30.
[4].  Duffy, J.P., et al., The Discovery of VX-745: A Novel and Selective p38alpha Kinase Inhibitor. ACS Med Chem Lett, 2011. 2(10): p. 758-63.
[5].  Bagley, M.C., et al., Gram-scale synthesis of the p38alpha MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome. Future Med Chem, 2010. 2(9): p. 1417-27.