Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.

TitleRationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.
Publication TypeJournal Article
Year of Publication2016
AuthorsCárdenas MG, Yu W, Béguelin W, Teater MR, Geng H, Goldstein RL, Oswald E, Hatzi K, Yang S-N, Cohen J, Shaknovich R, Vanommeslaeghe K, Cheng H, Liang D, Cho HJe, Abbott J, Tam W, Du W, Leonard JP, Elemento O, Cerchietti L, Cierpicki T, Xue F, MacKerell AD, Melnick AM
JournalJ Clin Invest
Date Published2016 09 01
KeywordsAnimals, Antineoplastic Agents, Cell Line, Tumor, Doxorubicin, Drug Design, Drug Screening Assays, Antitumor, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Indoles, Ligands, Lymphoma, Large B-Cell, Diffuse, Magnetic Resonance Spectroscopy, Male, Mice, Mice, SCID, Neoplasm Transplantation, Protein Binding, Proto-Oncogene Proteins c-bcl-6, Thiazolidinediones, Translocation, Genetic

Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.

Alternate JournalJ. Clin. Invest.
PubMed ID27482887
PubMed Central IDPMC5004937
Grant ListR01 CA194547 / CA / NCI NIH HHS / United States