DNA-encoded library yields oral brain-penetrant CHI3L1 modulator for Alzheimer's
- A very large DNA-encoded library screen yielded DELC2, a brain-penetrant compound that binds the glycan-recognition groove of CHI3L1 and blocks its interaction with RAGE.
- In glial cultures it dampened inflammatory signaling, lowered a reactive microglial marker and restored amyloid-beta uptake; CHI3L1 depletion and add-back supported on-target action.
- Oral dosing in 5xFAD mice gave sustained unbound brain exposure, better cognition, less amyloid-beta and calmer glial programs.
💡 Points
Sustained unbound brain exposure after oral dosing is the part I'd trust first, since it lets the cognitive benefit be read against actual target occupancy rather than assumed. Still open: human genetic support for blocking CHI3L1–RAGE, and whether the in vivo benefit tracks engagement of CHI3L1 itself. An aggressive amyloid mouse is a forgiving model, and this is an unreviewed preprint.