Inhibition of MK2 has been shown to offer advantages over that of
p38 MAPK in the development of cures for inflammatory diseases such as
arthritis.
P38 MAPK knockout in mice was lethal, whereas MK2-null mice demonstrated strong inhibition of
disease progression in
collagen-induced arthritis and appeared normal and viable. However, it is challenging to develop
ATP-competitive MK2 inhibitors due to high
ATP binding affinity to the
kinase. Non-
ATP-competitive MK2 inhibitors interact and bind to the
kinase in a mode independent of
ATP concentration, which could provide better selectivity and cellular potency. Therefore, it is desirable to identify non-
ATP-competitive MK2 inhibitors. Through structure optimization of lead compound 1, a novel series of dihydrooxadiazoles was discovered. Additional structure-activity relationship (SAR) study of this series led to the identification of compound 38 as a non-
ATP-competitive MK2 inhibitor with potent enzymatic activity and good cellular potency. The SAR, synthesis, and
biological data of dihydrooxadiazole series are discussed.