Discovery of a B-Cell Lymphoma 6 Protein-Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach.
J Med Chem
; 60(10): 4358-4368, 2017 05 25.
Article
en En
| MEDLINE
| ID: mdl-28471657
ABSTRACT
B-cell lymphoma 6 (BCL6) is a transcriptional factor that expresses in lymphocytes and regulates the differentiation and proliferation of lymphocytes. Therefore, BCL6 is a therapeutic target for autoimmune diseases and cancer treatment. This report presents the discovery of BCL6-corepressor interaction inhibitors by using a biophysics-driven fragment-based approach. Using the surface plasmon resonance (SPR)-based fragment screening, we successfully identified fragment 1 (SPR KD = 1200 µM, ligand efficiency (LE) = 0.28), a competitive binder to the natural ligand BCoR peptide. Moreover, we elaborated 1 into the more potent compound 7 (SPR KD = 0.078 µM, LE = 0.37, cell-free protein-protein interaction (PPI) IC50 = 0.48 µM (ELISA), cellular PPI IC50 = 8.6 µM (M2H)) by a structure-based design and structural integration with a second high-throughput screening hit.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Proto-Oncogénicas c-bcl-6
/
Bibliotecas de Moléculas Pequeñas
/
Mapas de Interacción de Proteínas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Japón