Trisubstituted 1,3,5-Triazines: The First Ligands of the sY12-Binding Pocket on Chemokine CXCL12

CXCL12, a CXC-type chemokine, binds its receptor CXCR4, and the resulting signaling cascade is essential during development and subsequently in immune function. Pathologically, the CXCL12–CXCR4 signaling axis is involved in many cancers and inflammatory diseases and thus has sparked continued interest in the development of therapeutics. Small molecules targeting CXCR4 have had mixed results in clinical trials. Alternatively, small molecules targeting the chemokine instead of the receptor provide a largely unexplored space for therapeutic development. Here we report that trisubstituted 1,3,5-triazines are competent ligands for the sY12-binding pocket of CXCL12. The initial hit was optimized to be more synthetically tractable. Fifty unique triazines were synthesized, and the structure–activity relationship was probed. Using computational modeling, we suggest key structural interactions that are responsible for ligand–chemokine binding. The lipophilic ligand efficiency was improved, resulting in more soluble, drug-like molecules with chemical handles for future development and structural studies.