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-γ secretion and promotes tumor cell killing in
cocultures 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.