Turning EGFR kinase inhibitors into BAX inhibitors with the kinase activity engineered out
- A virtual screen flagged EGFR inhibitors, including dacomitinib and gefitinib-like cores, as possible BAX binders.
- Systematic modification built a first SAR for BAX inhibition and reduced EGFR kinase activity considerably.
- The series showed better BAX inhibition in vitro, in cells and in iPSC-derived brain organoids, with drug-like properties.
💡 Points
Inhibiting an executioner protein like BAX is hard, so starting from a privileged kinase scaffold is pragmatic. The real test is whether the EGFR activity is gone enough: a cytoprotectant that still hits kinases is a poor neuroprotective. I'd like orthogonal proof of direct BAX engagement and a broader kinome panel.