Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Cell Rep ; 20(12): 2860-2875, 2017 Sep 19.
Article in English | MEDLINE | ID: mdl-28930682

ABSTRACT

The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.


Subject(s)
Proteolysis , Proto-Oncogene Proteins c-bcl-6/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , DNA/metabolism , Gene Expression Regulation, Neoplastic/drug effects , HEK293 Cells , Humans , Inhibitory Concentration 50 , Kinetics , Models, Molecular , Proteasome Endopeptidase Complex/metabolism , Protein Binding/drug effects , Protein Domains , Proteolysis/drug effects , Proto-Oncogene Proteins c-bcl-6/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-6/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Ubiquitination/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL
...