BCI inhibits MKP3 by targeting the kinase-binding domain and disrupting ERK2 interaction.

ABSTRACT: Mitogen-activated protein kinase phosphatase 3 (MKP3), also known as dual-specificity phosphatase 6, is a critical regulator of extracellular signal-regulated kinase (ERK) signaling, and its dysregulation is implicated in diseases, such as cancer. The small-molecule inhibitor BCI ((E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one) has been reported to inhibit MKP3, thereby enhancing ERK signaling and promoting selective cytotoxicity in cancer cells. However, the molecular mechanism underlying BCI-mediated MKP3 inhibition remains unclear. In this research, we characterized the interaction between BCI and MKP3 using NMR titration, microscale thermophoresis, enzymatic assays, and AlphaFold 3 modeling. Our results demonstrate that BCI selectively binds to the kinase-binding doma

SUBMITTER: Qiu SJ 

PROVIDER: S-EPMC12444472 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature