Discovery and Optimization of LAG-3-Targeted Small Molecules via DNA-Encoded Chemical Library (DEL) Screening for Cancer Immunotherapy

Lymphocyte activation gene-3 protein (LAG-3) is an immune checkpoint receptor that promotes T cell exhaustion and immune evasion in cancer. While antibody-based LAG-3 inhibitors have reached the clinic, small molecule modulators remain unexplored. Here, we report compound 11, the most potent small molecule LAG-3 inhibitor to date. Identified via a 4.2-billion compound DNA-encoded chemical library (DEL) screen, compound 11 binds LAG-3 with submicromolar affinity and disrupts the LAG-3/MHCII interaction. Molecular modeling suggests direct antagonism at the LAG-3/MHCII interface with potential allosteric effects. In functional assays, compound 11 enhances IFN-{gamma} secretion and promotes tumor cell killing in co-cultures of PBMCs and cancer cells. Importantly, compound 11 also exhibits favorable pharmacokinetics. These findings support the development of small molecule LAG-3 inhibitors as immunotherapeutic agents and provide a foundation for further optimization. Table of Contents artwork O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/668839v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@248c84org.highwire.dtl.DTLVardef@185510forg.highwire.dtl.DTLVardef@18cce50org.highwire.dtl.DTLVardef@13cfd8c_HPS_FORMAT_FIGEXP M_FIG C_FIG