9AWX

Structure of full-length amyloidogenic immunoglobulin light chain H9 in complex with 1-(1-(imidazo[1,5-a]pyrazin-8-yl)azetidin-3-yl)-3-(2-(6-methyl-4-(3-methyl-3-phenylpyrrolidin-1-yl)-2-oxopyridin-1(2H)-yl)ethyl)urea

This is a non-PDB format compatible entry.

Summary for 9AWX

• Entry DOI: 10.2210/pdb9awx/pdb
• Descriptor: H9 Immunoglobulin Light Chain, PHOSPHATE ION, N-{1-[(4R)-imidazo[1,5-a]pyrazin-8-yl]azetidin-3-yl}-N'-(2-{6-methyl-4-[(3R)-3-methyl-3-phenylpyrrolidin-1-yl]-2-oxopyridin-1(2H)-yl}ethyl)urea, ... (4 entities in total)
• Functional Keywords: light chain dimer, amyloid, immune system
• Biological source: Homo sapiens
• Total number of polymer chains: 4
• Total formula weight: 91916.70

Authors

Lederberg, O.L.,Yan, N.L.,Stanfield, R.L.,Wilson, I.A.,Kelly, J.W. (deposition date: 2024-03-05, release date: 2024-12-18, Last modification date: 2024-12-25)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.81 Å)