TitleA small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo.
Publication TypeJournal Article
Year of Publication2010
AuthorsCerchietti, Leandro C., Ghetu Alexandru F., Zhu Xiao, Da Silva Gustavo F., Zhong Shijun, Matthews Marilyn, Bunting Karen L., Polo Jose M., Far├Ęs Christophe, Arrowsmith Cheryl H., Yang Shao Ning, Garcia Monica, Coop Andrew, MacKerell Alexander D., Prive Gilbert G., and Melnick Ari
JournalCancer Cell
Volume17
Issue4
Pagination400-11
Date Published2010 Apr 13
ISSN1878-3686
KeywordsAnimals, Cell Division, Cell Survival, Crystallography, X-Ray, Humans, Lymphoma, Large B-Cell, Diffuse, Mice, Mice, Inbred C57BL, Models, Molecular, Protein Conformation, Proto-Oncogene Proteins, Repressor Proteins, Transcription, Genetic, Zinc Fingers
Abstract

<p>The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.</p>

DOI10.1016/j.ccr.2009.12.050
Alternate JournalCancer Cell
PubMed ID20385364
PubMed Central IDPMC2858395
Grant ListR01 CA107331 / CA / NCI NIH HHS / United States
CA107331 / CA / NCI NIH HHS / United States
CA120215 / CA / NCI NIH HHS / United States
R01 CA120215 / CA / NCI NIH HHS / United States
R21 HL082670 / HL / NHLBI NIH HHS / United States
R56 CA104348-06 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States
HL082670 / HL / NHLBI NIH HHS / United States
R56 CA104348 / CA / NCI NIH HHS / United States