Non-ATP-competitive MKK3 modulators suppress TNF-α in mouse colitis models
- ATP-competitive p38 inhibitors failed in the clinic partly through poor kinome selectivity, so the authors targeted the upstream kinase MKK3 through a non-ATP-competitive pocket.
- The lead, (R)-48, suppressed TNF-α production, was highly orally bioavailable and showed dose-dependent efficacy with clear PK/PD relationships in mouse ulcerative colitis models.
- Biophysical data (HDX-MS) were used to probe how the compounds engage MKK3.
💡 Points
Moving one node upstream of p38 is a sensible way around the selectivity problem that sank the first-generation inhibitors. An oral, TNF-lowering small molecule for UC would be a genuinely different option next to injectable biologics. My concern is the allosteric pocket: SAR for non-ATP-site kinase binders can be steep and hard to translate between species, so I'd check the human-protein data early.