FEP+ calculations predict a stereochemical SAR switch for first-in-class indoline NIK inhibitors for multiple myeloma

In the search for first-in-class NIK inhibitors for multiple myeloma, we discovered an azaindoline hit class generated from a biochemical NIK autophosphorylation high-throughput screening assay which was optimized to the final cyanoindoline compound class. During the hit-to-lead phase, a prominent stereochemical SAR switch was observed which was accurately predicted by in silico FEP+ calculations. Crystallographic and computational analysis showed that for both stereoisomers comparable contacts, both in nature and number, could be formed by the switching hydroxyl group, making this system particularly interesting from an interaction energy viewpoint. We provide a detailed analysis of our FEP+ and WaterMap calculations and show how this type of computational chemistry methods are useful during hit-to-lead and lead optimization phases.