Advances in Small-Molecule Inhibitors of MKK4 and MKK7: From Structural Biology to Therapeutic Applications

The c-Jun N-terminal kinase (JNK) signaling cascade is a central regulator of cellular stress responses and a validated therapeutic target for diverse pathologies, including neurodegeneration, fibrosis, and cancer. However, the development of direct JNK inhibitors has been impeded by challenges regarding isoform selectivity and on-target toxicity. Consequently, medicinal chemistry efforts have shifted upstream to the "gatekeepers" of the pathway: the dual-specificity kinases MKK4 and MKK7. This review provides a comprehensive analysis of the structural biology, physiological functions, and pharmacological inhibition of these critical signaling nodes. We highlight the non-redundant therapeutic potential of these kinases, contrasting the role of MKK4 inhibition in unlocking liver regeneration with the utility of MKK7 inhibition in suppressing fibrosis and chronic inflammation. A systematic overview of small-molecule inhibitors is presented. For MKK4, we discuss the evolution from early promiscuous chemotypes to the first-in-class clinical candidate HRX215, which has demonstrated safety and efficacy in promoting hepatocyte proliferation. For MKK7, we examine the design of covalent inhibitors exploiting the unique hinge-region cysteine (Cys218), as well as emerging modalities such as lysine-targeting binders and peptide inhibitors disrupting protein-protein interactions. Finally, we discuss remaining challenges and future opportunities, including the development of dual inhibitors and proteolysis-targeting chimeras (PROTACs), to fully exploit the therapeutic value of the MKK4/7-JNK axis.