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Updated: Jul 30, 2025
Isolation and Activation of Murine Lymphocytes
Published on: October 30, 2016
Discovery of First-in-Class Small Molecule Inhibitors of Lymphocyte Activation Gene 3 (LAG-3)
Somaya A Abdel-Rahman1,2, Ashfaq Ur Rehman3, Moustafa T Gabr1
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York 10065, United States.
Abstract:
Lymphocyte activation gene 3 (LAG-3) is a negative immune checkpoint that plays a key role in downregulating the immune response to cancer. Inhibition of LAG-3 interactions allows T cells to regain cytotoxic activity and reduce the immunosuppressive function of regulating T cells. We utilized a combination approach of focused screening and "SAR by catalog" to identify small molecules that function as dual inhibitors of the interactions of LAG-3 with major histocompatibility complex (MHC) class II and fibrinogen-like protein 1 (FGL1). Our top hit compound inhibited both LAG-3/MHCII and LAG-3/FGL1 interactions in biochemical binding assays with IC50 values of 4.21 ± 0.84 and 6.52 ± 0.47 μM, respectively. Moreover, we have demonstrated the ability of our top hit compound to block LAG-3 interactions in cell-based assays. This work will pave the way for future drug discovery efforts aiming at the development of LAG-3-based small molecules for cancer immunotherapy.
Insights
Researchers identified small molecules that inhibit Lymphocyte Activation Gene 3 (LAG-3) interactions. This dual inhibition of LAG-3/MHCII and LAG-3/FGL1 interactions may advance cancer immunotherapy drug discovery.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Lymphocyte Activation Gene 3 (LAG-3) is a critical negative immune checkpoint regulating anti-cancer immune responses.
- LAG-3 signaling suppresses T cell activity and promotes immunosuppression via interactions with MHC class II and FGL1.
- Overcoming LAG-3-mediated inhibition is a key strategy for enhancing cancer immunotherapy.
Purpose of the Study:
- To identify novel small molecules that simultaneously inhibit the interactions of LAG-3 with its ligands, MHC class II and FGL1.
- To develop dual inhibitors targeting LAG-3 for potential application in cancer immunotherapy.
Main Methods:
- Employed a combination of focused screening and Structure-Activity Relationship (SAR) by catalog approaches.
- Utilized biochemical binding assays to quantify inhibition of LAG-3/MHCII and LAG-3/FGL1 interactions.
- Validated compound efficacy in cell-based assays to confirm blockade of LAG-3 interactions.
Main Results:
- Identified a top-hit small molecule compound with dual inhibitory activity against LAG-3/MHCII and LAG-3/FGL1 interactions.
- The lead compound demonstrated IC50 values of 4.21 ± 0.84 μM for LAG-3/MHCII and 6.52 ± 0.47 μM for LAG-3/FGL1 in biochemical assays.
- Confirmed the compound's ability to inhibit LAG-3 interactions in relevant cell-based models.
Conclusions:
- The identified small molecule represents a promising lead for developing novel LAG-3-targeting cancer immunotherapies.
- This dual-acting inhibitor has the potential to restore T cell-mediated anti-tumor immunity.
- Further preclinical development of these LAG-3 small molecule inhibitors is warranted for cancer treatment.
