.png){kind=icon}
.png){kind=icon}
Return
Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains
.png){kind=icon}
PRE
AI
DOI：10.1021/acs.jmedchem.4c01773.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
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 lambda 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 lambda 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 lambda 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.
Keywords:
PROTEIN-BINDING
Journal
IF:
6.8
Papers:
2.7W
Citations:
9.4W