Mitogen-activated protein kinase kinase 7 – Growth arrest and DNA damage-inducible protein 45 beta protein–protein interaction site (MKK7–GADD45β PPI site)

The MKK7–GADD45β protein–protein interaction (PPI) site is a specialized therapeutic target primarily relevant in the treatment of Multiple Myeloma and other NF-κB-driven malignancies. In these disease states, the NF-κB pathway induces the expression of GADD45β, which subsequently binds to and inhibits the kinase MKK7 (Mitogen-activated protein kinase kinase 7), a crucial mediator of the pro-apoptotic JNK signaling cascade (Papa et al., 2014; UniProt: O14733). This interaction serves as a survival mechanism for cancer cells by suppressing apoptosis. Therapeutic intervention focuses on disrupting this specific PPI using small molecules or peptides, such as the D-tripeptide DTP3, which binds to MKK7 and prevents GADD45β from docking (Tornatore et al., 2014). By releasing the "brake" on MKK7, these inhibitors restore JNK-mediated cell death specifically in malignant cells that are "addicted" to this survival signal. This target is highly valued for its potential to provide high selectivity and low toxicity compared to broader kinase inhibitors (ClinicalTrials.gov: NCT02431260).

Other names

MAP2K7–GADD45B interaction siteGADD45β/MKK7 complexMKK7–GADD45β interfaceGADD45B–MAP2K7 PPI

Small-molecule inhibition of the protein–protein interaction between GADD45β and MKK7, which restores MKK7 enzymatic activity and triggers JNK-dependent apoptosis in cancer cells.