Structural Insights on the Role of Halogen Bonding in Protein MEK Kinase-Inhibitor Complexes.
Pietro MilesiFrancesca Baldelli BombelliLuisa LanfranconeRosa M GomilaAntonio FronteraPierangelo MetrangoloGiancarlo TerraneoPublished in: Chemistry, an Asian journal (2024)
Kinases are enzymes that play a critical role in governing essential biological processes. Due to their pivotal involvement in cancer cell signaling, they have become key targets in the development of anti-cancer drugs. Among these drugs, those containing the 2,4-dihalophenyl moiety demonstrated significant potential. Here we show how this moiety, particularly the 2-fluoro-4-iodophenyl one, is crucial for the structural stability of the formed drug-enzyme complexes. Crystallographic analysis of reported kinase-inhibitor complex structures highlights the role of the halogen bonding that this moiety forms with specific residues of the kinase binding site. This interaction is not limited to FDA-approved MEK inhibitors, but it is also relevant for other kinase inhibitors, indicating its broad relevance in the design of this class of drugs.