AI Insight
Researchers developed a high-throughput TR-FRET assay to study the interaction between LILRB4 (ILT3), an inhibitory immune checkpoint receptor on myeloid cells, and its recently identified ligand Secretogranin 2 (SCG2). The assay was validated using a blocking antibody and confirmed through orthogonal ELISA measurements, demonstrating reliable performance. Pilot screening of chemical libraries identified two compounds, BMS-813160 and PSB-603, with reproducible dose-dependent inhibition of the LILRB4-SCG2 interaction at IC50 values of 26.7 micromolar and 37.2 micromolar, respectively.
Why it matters
LILRB4-mediated immunosuppression in the tumor microenvironment represents a clinically relevant but underexplored target, and this assay platform provides a practical foundation for discovering small molecule drugs that could complement or improve upon existing immunotherapy approaches. Identifying first-in-class inhibitors of myeloid-driven immune suppression may open new therapeutic avenues for cancer treatment.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Leukocyte immunoglobulin-like receptor B4 (LILRB4, ILT3) is an inhibitory immune checkpoint expressed on myeloid cells, where it contributes to immunosuppression within the tumor microenvironment. Secretogranin 2 (SCG2) has recently been identified as a functional ligand of LILRB4, yet small molecule modulators of this interaction remain unexplored. Here, we report the development of a high-throughput time-resolved fluorescence resonance energy transfer (TR-FRET) assay to interrogate the LILRB4 (ILT3)-SCG2 interaction. The assay demonstrated robust performance and was validated using a blocking anti-LILRB4 antibody, consistent with orthogonal ELISA measurements. Pilot screening of chemical libraries identified 23 primary hits, of which two compounds, BMS-813160 and PSB-603, showed reproducible, dose-dependent inhibition with TR-FRET IC values of 26.7 M and 37.2 M, respectively. Activity was confirmed by ELISA, supporting the robustness of the assay. This platform enables high-throughput discovery of first-in-class small molecule modulators of the LILRB4-SCG2 immune checkpoint and provides a foundation for targeting myeloid-driven immunosuppression.