Structural insights on the role of halogen bonding in protein MEK kinase-inhibitor complexes

Kinases are enzymes that play a critical role in governingessential biological processes. Due to their pivotal involvementin cancer cell signaling, they have become key targets in thedevelopment of anti-cancer drugs. Among these drugs, thosecontaining the 2,4-dihalophenyl moiety demonstrated signifi-cant potential. Here we show how this moiety, particularly the2-fluoro-4-iodophenyl one, is crucial for the structural stabilityof the formed drug-enzyme complexes. Crystallographic analy-sis of reported kinase-inhibitor complex structures highlightsthe role of the halogen bonding that this moiety forms withspecific residues of the kinase binding site. This interaction isnot limited to FDA-approved MEK inhibitors, but it is alsorelevant for other kinase inhibitors, indicating its broadrelevance in the design of this class of drugs