Crystal Structures of Diaryl Hydrazone and Sulfone Stabilizers in Complex with an Amyloidogenic Light Chain Reveal an Alternate Ligand‐Binding Cavity

Abstract

AbstractStabilization of amyloidogenic immunoglobulin light chains (LCs) by binding of small molecule “kinetic stabilizers” is under development as a novel treatment for light chain amyloidosis. From a high‐throughput screen, we previously identified 16 full‐length (FL) LC stabilizers from five distinct chemotypes. We then obtained structural biological information on two classes of hits, coumarins and hydantoins, revealing that both chemotypes bind to a pocket at the VL−VL interface of the FL LC dimer. Here, we report crystal structures of three screening hits from two other chemotypes, diaryl hydrazones and sulfones, in complex with an amyloidogenic FL LC. While two of these hits bind to the previously identified pocket, one diaryl hydrazone binds to a different pocket bisected by the C2 symmetry axis of the dimer. These data further expand on the FL LC stabilizer‐binding surface that could be used in design of more potent FL LC aggregation inhibitors.