Deciphering the Structure-Activity Relationships Underpinning the Linkerology of Bivalent EGFR Inhibitors

Linking small molecules that bind adjacent sites on a target is a promising strategy for developing compounds with tight binding affinities. ATP-allosteric bivalent inhibitors (AABIs) of the epidermal growth factor receptor (EGFR) have provided new insights into efficient linker design where large potency gains can be achieved through particular design scenarios. In this work, we systematically evaluated the structure-activity relationships of target molecules to better understand the most effective approach to maximizing potency through linker optimization. Our results show that linker length and points of connection are both important strategies for significant potency enhancements. Structures and simulations indicate that maximal flexibility is likely the most important design criterion for linking molecules that occupy adjacent pockets, as modeled by the EGFR kinase domain. These studies provide a general framework for the rational design of linkers broadly relevant to fragment-based drug discovery and a number of related scenarios in medicinal chemistry.