9AX2

Structure of full-length amyloidogenic immunoglobulin light chain H9 in complex with 2-(1-methyl-3-oxo-5-(2-phenylpropoxy)isoindolin-2-yl)ethyl (3-(1H-imidazol-4-yl)benzyl)carbamate

これはPDB形式変換不可エントリーです。

9AX2 の概要

• エントリーDOI: 10.2210/pdb9ax2/pdb
• 分子名称: H9 Immunoglobulin Light Chain, 2-{(1R)-1-methyl-3-oxo-5-[(2S)-2-phenylpropoxy]-1,3-dihydro-2H-isoindol-2-yl}ethyl {[(3M)-3-(1H-imidazol-4-yl)phenyl]methyl}carbamate, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: light chain dimer, amyloid, immune system
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 91437.79

構造登録者

Lederberg, O.L.,Yan, N.L.,Stanfield, R.L.,Wilson, I.A.,Kelly, J.W. (登録日: 2024-03-05, 公開日: 2024-12-18, 最終更新日: 2024-12-25)

主引用文献

Lederberg, O.L.,Yan, N.L.,Sanchez, J.,Ren, W.,Ash, C.,Wilkens, S.J.,Qiu, H.,Qin, B.,Grant, V.H.,Jackman, A.B.,Stanfield, R.L.,Wilson, I.A.,Petrassi, H.M.,Rhoades, D.,Kelly, J.W.
Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains.
J.Med.Chem., 67:21070-21105, 2024

PubMed 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 LC) 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 LC 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 LCs 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.

PubMed: 39626211
DOI: 10.1021/acs.jmedchem.4c01773

実験手法

X-RAY DIFFRACTION (1.94 Å)