Discovery of First-in-Class Small Molecule Inhibitors of Lymphocyte Activation Gene 3 (LAG-3)

Somaya A Abdel-Rahman; Ashfaq Ur Rehman; Moustafa T Gabr

doi:10.1021/acsmedchemlett.3c00054

Discovery of First-in-Class Small Molecule Inhibitors of Lymphocyte Activation Gene 3 (LAG-3)

ACS Med Chem Lett. 2023 Apr 11;14(5):629-635. doi: 10.1021/acsmedchemlett.3c00054. eCollection 2023 May 11.

Authors

Somaya A Abdel-Rahman^{1

2}, Ashfaq Ur Rehman³, Moustafa T Gabr¹

Affiliations

¹ Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York 10065, United States.
² Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
³ Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697, United States.

PMID: 37197466
PMCID: PMC10184155 (available on 2024-05-11)
DOI: 10.1021/acsmedchemlett.3c00054

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.