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

Yan, Nicholas L.; Wilson, Ian A.; Kelly, Jeffery W.

doi:10.1002/ijch.202300002

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

Journal Article · Wed Apr 12 00:00:00 EDT 2023 · Israel Journal of Chemistry

DOI:https://doi.org/10.1002/ijch.202300002· OSTI ID:1969593

^[1]; ^[2]; Kelly, Jeffery W. ^[3]

Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla CA 92037 USA
Department of Integrative Structural and Computational Biology The Scripps Research Institute La Jolla CA 92037 USA, The Skaggs Institute for Chemical Biology The Scripps Research Institute La Jolla CA 92037 USA
Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla CA 92037 USA, The Skaggs Institute for Chemical Biology The Scripps Research Institute La Jolla CA 92037 USA

Abstract

Stabilization 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 V _L −V _L 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 C ₂ 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1969593

Alternate ID(s):: OSTI ID: 1969595
OSTI ID: 2580620

Journal Information:: Israel Journal of Chemistry, Journal Name: Israel Journal of Chemistry Journal Issue: 10-11 Vol. 63; ISSN 0021-2148

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Israel

Language:: English

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