Breakthrough in Cancer Immunotherapy: Discovery of LAG-3 Inhibitor Shows Promise

Researchers at Weill Cornell Medicine have made a significant breakthrough in cancer immunotherapy, discovering a potent small molecule inhibitor of the lymphocyte activation gene-3 (LAG-3) protein. The novel compound, identified through a DNA-encoded chemical library (DEL) screen, exhibits submicromolar affinity for LAG-3 and disrupts the LAG-3/MHCII interaction, which plays a crucial role in cancer evasion. The research holds promise for the development of small molecule LAG-3 inhibitors as immunotherapeutic agents.

Key Takeaways:

• The study reported the discovery of a novel small molecule LAG-3 inhibitor, compound , which binds LAG-3 with submicromolar affinity and disrupts the LAG-3/MHCII interaction.
• The compound enhances IFN-g secretion and promotes tumor cell killing in cocultures of peripheral blood mononuclear cells (PBMCs) and cancer cells.
• Molecular modeling suggests direct antagonism at the LAG-3/MHCII interface with potential allosteric effects.
• The research concluded that these findings support the development of small molecule LAG-3 inhibitors as immunotherapeutic agents and provide a foundation for further optimization.
• The compound exhibits favorable pharmacokinetics.
• The study utilized a 4.2-billion compound DNA-encoded chemical library (DEL) screen to identify the novel inhibitor.
• Authors Laura Calvo-Barreiro, Somaya A. Abdel-Rahman, Nelson Garcia Vazquez, Hossam Nada, and Moustafa T. Gabr contributed to the research.

Statistics:

• The compound was identified through a 4.2-billion compound DNA-encoded chemical library (DEL) screen.
• The compound binds LAG-3 with submicromolar affinity (sub 1 μM).
• Tumor cell killing in cocultures of PBMCs and cancer cells was enhanced by the compound.
• The compound exhibits favorable pharmacokinetics.
• The study provides a foundation for further optimization of small molecule LAG-3 inhibitors.

Sources:

• Journal of Medicinal Chemistry, "Discovery and Optimization of LAG-3-Targeted Small Molecules via DNA-Encoded Chemical Library (DEL) Screening for Cancer Immunotherapy", 2025.
• Journal of Medicinal Chemistry, "Amer Chemical Soc, 1155 16TH St, NW, Washington, DC 20036, USA" (publisher contact information).
• Immunotherapy Weekly, "NewsRx. New Cancer Study Findings Have Been Reported by Researchers at Weill Cornell Medicine [Discovery and Optimization of LAG-3-Targeted Small Molecules via DNA-Encoded Chemical Library (DEL) Screening for Cancer Immunotherapy]", September 3, 2025, p 2628.