Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma
Mariano G. Cardenas, … , Alexander D. MacKerell Jr., Ari M. Melnick
Mariano G. Cardenas, … , Alexander D. MacKerell Jr., Ari M. Melnick
Published August 2, 2016
Citation Information: J Clin Invest. 2016;126(9):3351-3362. https://doi.org/10.1172/JCI85795.
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Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma

Abstract

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.

Authors

Mariano G. Cardenas, Wenbo Yu, Wendy Beguelin, Matthew R. Teater, Huimin Geng, Rebecca L. Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyo Je Cho, Joshua Abbott, Wayne Tam, Wei Du, John P. Leonard, Olivier Elemento, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell Jr., Ari M. Melnick

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Figure 4

FX1 selectively suppresses BCL6-dependent GCB-DLBCL growth in vitro and in vivo.

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FX1 selectively suppresses BCL6-dependent GCB-DLBCL growth in vitro and ...
(A) Viability of BCL6-dependent and -independent DLBCL cell lines after 48 hours of treatment with different concentrations of FX1 based on resazurin reduction. The y axis shows percentage of growth-suppressing effect of the compound compared with vehicle-treated cells. Effect = 100% – 100% × (fluorescence of FX1-treated cells/fluorescence of vehicle-treated cells). The graph represents average of 3 independent experiments, and the GI50 values represent mean ± SD of 3 biological replicates. (B) Tumor volume of established OCI-Ly7 xenografts implanted in SCID mice treated with daily injections of 25 or 50 mg/kg 79-6 or FX1 versus vehicle for 10 days (n = 10 mice per group, 2-tailed Mann-Whitney unpaired test). (C) Tumor burden AUC was calculated from the same mice as in B between the initial tumor volume (t0: 100 mm3) and the final volume at day 9 (n = 10 mice per group, 2-tailed Mann-Whitney unpaired test). Values in B and C are shown as mean ± SEM.