Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains

  • J Med Chem. 2024 Dec 12;67(23):21070-21105. doi: 10.1021/acs.jmedchem.4c01773.
Oren L Lederberg  1 ,  Nicholas L Yan  1 ,  Julian Sanchez  1 ,  Wen Ren  1 ,  Carl Ash  1 ,  Steven J Wilkens  2 ,  Huang Qiu  2 ,  Bo Qin  2 ,  Virginia H Grant  2 ,  Alex B Jackman  2 ,  Robyn L Stanfield  3 ,  Ian A Wilson  3  4 ,  H Michael Petrassi  2 ,  Derek Rhoades  1 ,  Jeffery W Kelly  1  4
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
  • 2. Protego Biopharma, 10945 Vista Sorrento Parkway, San Diego, California 92130, United States.
  • 3. Department of Integrative Structural and Computational Biology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States.
  • 4. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road., La Jolla, California 92037, United States.
PMID: 39626211 DOI: 10.1021/acs.jmedchem.4c01773
Abstract

Kinetic stabilization of amyloidogenic immunoglobulin light chains (LCs) through small molecule binding may become the first treatment for the proteinopathy component of light chain amyloidosis (AL). Kinetic stabilizers selectively bind to the native state over the misfolding transition state, slowing denaturation. Prior λ full-length LC dimer (FL LC2) kinetic stabilizers exhibited considerable plasma protein binding. We hypothesized that the coumarin "aromatic core" of the stabilizers was responsible for the undesirable plasma protein binding. Here, we describe structure-activity relationship (SAR) data initially focused on replacing the coumarin aromatic core. 2-pyridones proved suitable replacements. We subsequently optimized the "anchor substructure" in the context of 2-pyridones, resulting in potent λ FL LC2 kinetic stabilizers exhibiting reduced plasma protein binding. The 3-methyl- or 3-ethyl-3-phenylpyrrolidine-2-pyridone scaffold stabilized multiple AL patient-derived λ FL LC2s in human plasma. This, coupled with X-ray crystallographic data, indicates that 3-alkyl-3-phenylpyrrolidine-2-pyridone-based stabilizers are promising candidates for treating the proteinopathy component of AL.

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