From Virtual Screens to Cellular Target Engagement: New Small Molecule Ligands for the Immune Checkpoint LAG-3.
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Fuchs N, Calvo-Barreiro L, Talagayev V, Pach S, Wolber G, Gabr MT
ACS Med. Chem. Lett. 15 (11) 1884-1890 [2024-11-14; online 2024-10-15]
Herein, we performed a virtual screening study to discover new scaffolds for small molecule-based ligands of the immune checkpoint lymphocyte-activation gene 3 (LAG-3). Molecular dynamics (MD) simulations using the LAG-3 structure revealed two putative binding sites for small molecules: the antibody interface and the lipophilic canyon. A 3D pharmacophore screening resulted in the identification of potential ligands for these binding sites and afforded a library of 25 compounds. We then evaluated the screening hits for LAG-3 binding via microscale thermophoresis (MST) and surface plasmon resonance (SPR). Our biophysical screening identified two binders with K D values in the low micromolar range, compounds 3 (antibody interface) and 25 (lipophilic canyon). Furthermore, we investigated the ability of LAG-3 hits to engage LAG-3 on a cellular level using a cellular thermal shift assay (CETSA). In summary, compound 3 shows potential as a lead but is not yet a development candidate.
PubMed 39563794
DOI 10.1021/acsmedchemlett.4c00350
Crossref 10.1021/acsmedchemlett.4c00350