Discovery of Highly Selective Inhibitors of the Human Constitutive Proteasome ß5c Chymotryptic Subunit.
J Med Chem
; 66(2): 1172-1185, 2023 01 26.
Article
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| MEDLINE
| ID: mdl-36608337
We describe our discovery and development of potent and highly selective inhibitors of human constitutive proteasome chymotryptic activity (ß5c). Structure-activity relationship studies of the novel class of inhibitors focused on optimization of N-cap, C-cap, and side chain of the chemophore asparagine. Compound 32 is the most potent and selective ß5c inhibitor in this study. A docking study provides a structure rationale for potency and selectivity. Kinetic studies show a reversible and noncompetitive inhibition mechanism. It enters the cells to engage the proteasome target, potently and selectively kills multiple myeloma cells, and does so by synergizing with a ß5i-selective inhibitor.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Asparagina
/
Complejo de la Endopetidasa Proteasomal
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2023
Tipo del documento:
Article