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Preprint WatchMildJune 24th, 2026

AI-Guided Discovery of Small Molecule LILRB4 (ILT3) Inhibitors Reprograms Microglia and Reduces Amyloid Pathology

Abdel-Rahman, S.; Gabr, M.

AI-guided small molecules that disrupt the LILRB4-ApoE interaction reprogram microglia, restore amyloid-beta uptake, and reduce amyloid burden in the 5xFAD model.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The one indexed LILRB4 failure on file is BND-35, an anti-LILRB4 myeloid-checkpoint antibody that was stopped in advanced solid tumors for strategic reasons (bnd-35-lilrb4-ilt3-myeloid-checkpoint-solid-tumors-phase1-strategic-termination). This preprint does not test that program. It reports AI-guided small molecules that block the LILRB4-ApoE interaction and restore amyloid-beta uptake in iPSC-derived microglia and the 5xFAD mouse, moving LILRB4 into a different modality and a different indication, Alzheimer's disease. It neither replicates nor contradicts the oncology termination, because the indexed failure was an antibody in solid tumors while the readouts here are neuroinflammatory. The relevance is that LILRB4 druggability is being pursued along a second axis even though the single indexed clinical attempt was halted on strategy rather than biology, which keeps the documented failure burden low and leaves open which disease setting actually rewards LILRB4 blockade.

Abstract excerpt

The inhibitory microglial receptor LILRB4 (ILT3) suppresses amyloid-beta clearance in Alzheimer's disease through ApoE-dependent signaling but remains undrugged by small molecules. Ultralarge-scale screening of about 500 million compounds identified small molecules that bind LILRB4 with nanomolar affinity and competitively block ApoE engagement. In human iPSC-derived microglia, LILRB4 inhibition suppressed SHP1/2-dependent signaling, attenuated NF-kB activation, and restored Abeta uptake; the lead compound improved cognition, reduced amyloid burden, and dampened neuroinflammation after oral dosing in the 5xFAD mouse model.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.