Distinct binding modes of a benzothiazole derivative confer structural bases for increasing ERK2 or p38α MAPK selectivity

Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2) and p38 alpha MAP kinase (p38 alpha MAPK), regulate various cellular responses. ERK2 is a drug target for treating many diseases, such as cancer, whereas p38 alpha has attracted much attention as a promising drug target for treating inflammatory disorders. ERK2 is a critical off-target for p38 alpha MAPK and vice versa. In this study, an allosteric ERK2 inhibitor with a benzothiazole moiety (compound 1) displayed comparable inhibitory activity against p38 alpha MAPK. Crystal structures of these MAPKs showed that compound 1 bound to the allosteric site of ERK2 and p38 alpha MAPK in distinct manners. Compound 1 formed a covalent bond with Cys162 of p38 alpha MAPK, whereas this covalent bond was absent in the ERK2 complex even though the corresponding cysteine is conserved in ERK2. Structural dissection combined with computational simulations indicated that an amino acid difference in the allosteric site is responsible for the distinct binding modes of compound 1 with ERK2 and p38 alpha MAPK. These structural insights underline the feasibility of developing highly selective and potent ERK2 and p38 alpha MAPK inhibitors.