# Targeting the JNK Gatekeepers: Structural Evolution and Medicinal Chemistry of MKK4 and MKK7 Inhibitors

## TL;DR

This paper reviews the development of inhibitors targeting MKK4 and MKK7, upstream regulators of the JNK pathway, for treating diseases like fibrosis and liver dysfunction.

## Contribution

The paper provides a critical review of structural and medicinal advances in MKK4 and MKK7 inhibitors, highlighting their distinct therapeutic potentials and design strategies.

## Key findings

- MKK4 inhibition is a promising strategy for liver regeneration, as demonstrated by HRX215.
- MKK7 inhibition is being explored for anti-fibrotic and anti-inflammatory applications.
- Structure-based design strategies, such as covalent targeting of MKK7's Cys218, improve inhibitor selectivity.

## Abstract

The c-Jun N-terminal kinase (JNK) pathway is a central driver of fibrosis, inflammation, and neurodegeneration. While direct JNK inhibitors have shown therapeutic promise, achieving high isoform selectivity remains a significant medicinal chemistry challenge. Furthermore, targeting the upstream ‘gatekeepers’ MKK4 and MKK7 offers a distinct mechanism to modulate pathway output with greater precision. Consequently, medicinal chemistry efforts have shifted upstream to the dual-specificity kinases MKK4 and MKK7. This review critically evaluates the structural biology and pharmacological evolution of small-molecule inhibitors targeting these nodes. We contrast the distinct therapeutic landscapes of the two kinases: while MKK4 inhibition has emerged as a breakthrough strategy for unlocking liver regeneration (exemplified by the first-in-class clinical candidate HRX215), MKK7 inhibition is primarily pursued for its anti-fibrotic and anti-inflammatory potential. Special attention is given to structure-based design strategies, including the exploitation of the unique hinge-region cysteine (Cys218) for MKK7-specific covalent targeting and the optimization of scaffold selectivity against off-targets like BRAF. Finally, we discuss emerging modalities, such as PROTACs and dual inhibitors, outlining a roadmap for the next generation of precision therapeutics targeting the MKK–JNK axis.