p38α is a member of the mitogen-activated protein kinase (MAPK) family of serine/threonine protein kinases. It is widely expressed in endothelial, immune, and inflammatory cells and plays a central role in the regulation of proinflammatory cytokine production including TNF-α, IL-1β, and IL-6. VX-745 is a potent inhibitor of p38α MAPK (IC50 = 10 nM) with 20-fold selectivity over p38β and 1000-fold selectivity over closely related kinases, ERK1 and JNK1-3. It blocks IL-1β and TNF-α release in whole blood in vitro with IC50 values of 150 and 180 nM, respectively. VX-745 has been shown to demonstrate anti-inflammatory efficacy in an animal model of rheumatoid arthritis, but was discontinued in clinical trial due to adverse central nervous system effects.
