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

Overview

abstract

  • 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.

publication date

  • August 20, 2025

Research

keywords

  • Antigens, CD
  • DNA
  • Drug Discovery
  • Immunotherapy
  • Neoplasms
  • Small Molecule Libraries

Identity

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.5c00995

PubMed ID

  • 40832692