Extended Data Fig. 1: Medicinal chemistry optimization schematic for the discovery of IK-595.

IK-595 was discovered through structure-activity relationship (SAR) optimization and was structurally enabled by x-ray analysis of MEK1 and BRAF co-crystals. Multiple known MEK binding chemical scaffolds including that of trametinib were used as starting points and informed the ultimate selection of IK-595. The SAR optimization focused on three key objectives; 1) identifying molecules that bound tightly within the MEK allosteric pocket, 2) identifying molecules that made tight interactions with the RAF isoforms, and 3) identifying molecules that had moderate pharmacokinetic clearance. The internal fused biaryl ring system of a trametinib-like chemical series that led to IK-595 was opened in order to enhance the pharmacokinetic clearance relative to closed ring molecules. Multiple heteroatom, alkyl, fluoroalkyl, nitrile, and ether substitutions in the core as well as heteroatom and ring size adjustments in the terminal ring system were explored to maximize MEK binding and to further optimize the pharmacokinetic profile. The addition of the cloro atom in the terminal ring system was key to achieving the optimal balance of clearance and off-rate binding. In addition, based on the binding orientation, both oxygens of the sulfamide group created hydrogen bonds with RAF thereby enabling IK-595’s ability to function as a tight MEK-RAF molecular glue.