Etrasimod-derived cyclopenta[b]indoles emerge as a new scaffold for dual MDM2/MDM4 inhibition and p53 activation
- Virtual screening against both MDM2 and MDM4 flagged the approved drug etrasimod as a dual binder.
- Structure-guided changes to its cyclopentyl group gave six cyclopenta[b]indole analogues aimed at the shared hydrophobic Leu-26 pocket.
- The 3,4-dichlorophenyl analogue was strongest, binding both proteins in the low-micromolar range, and in SJSA-1 cells it raised p53 and apoptosis markers.
💡 Points Based on the abstract
A fair starting point for a repurposed hit, but was the parent's S1P receptor activity engineered out? That off-target liability would follow the scaffold. SJSA-1 is MDM2-amplified and p53 wild-type, so a p53-null counter-screen should come first, along with a nutlin-class reference to show how large the potency gap really is.
📄 Paper · ACS Medicinal Chemistry Letters ↗ Discovery of a Novel Chemical Scaffold for Dual MDM2 and MDM4 Inhibition