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

• Published in: Journal of medicinal chemistry 2024-12, Vol.67 (23), p.21070-21105
• Main Authors: Lederberg, Oren L., Yan, Nicholas L., Sanchez, Julian, Ren, Wen, Ash, Carl, Wilkens, Steven J., Qiu, Huang, Qin, Bo, Grant, Virginia H., Jackman, Alex B., Stanfield, Robyn L., Wilson, Ian A., Petrassi, H. Michael, Rhoades, Derek, Kelly, Jeffery W.
• Format: Article
• Language: English
• Subjects: Amyloidosis - drug therapy; Amyloidosis - metabolism; Crystallography, X-Ray; Drug Discovery; Humans; Immunoglobulin Light Chains - chemistry; Immunoglobulin Light Chains - metabolism; Kinetics; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01773

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.