P38 MAPKs is a class of kinases responsive to stress stimuli. It has four types, including p38α (MAPK14), p38β (MAPK11), p38γ (MAPK12/ERK6), and p38δ (MAPK13/SAPK4). The kinases involve an inflammatory process. The previous study demonstrates that p38 inhibitors have a potential effect on autoimmune diseases and inflammation.

AMG-548, a potent p38α inhibitor, selectively inhibits p38α activity, with a Ki value of 0.5 nM. It is also slightly selective over p38β. The inhibitor shows little effect on p38β or p38δ compared to p38α. The corresponding Ki values are 3.6 nM, 2,600 nM and 4,100 nM. Besides, AMG-548 shows a Ki value of 5 nM for dog p38α.

Except for the high affinity to p38α, AMG-548 exhibits a modest inhibitory effect on JNKs. The Kis are 11480 nM, 39 nM and 61 nM for JNK1, JNK2, and JNK3, respectively. It also exhibits >1000 fold selectivity at p38α over ∼35 other kinases.

In addition, AMG-548 also inhibits several cytokines, such as TNFα, IL1β, IL-8, and IL-6. In the human whole blood, it suppresses LPS induced TNFα and IL1β and also inhibits TNFα induced IL-8 and IL1β induced IL-6. The IC50 values are 3 nM, 7 nM, 0.7 nM and 1.3 nM, respectively.

AMG-548 shows not only potent in vitro activity, but also excellent in vivo activity. It is protective in LPS induced TNFα production in mice and collagen-induced and adjuvant-induce arthritis in Lewis rats.

1. Lee MR, et al. Curr Med Chem. 2005;12(25):2979-94.