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

Cárdenas, Mariano; Yu, Wenbo; Béguelin, Wendy; Teater, Matt; Geng, Huimin; Goldstein, Ronald E.; Oswald, Erin; Hatzi, Katerina; Yang, Shao Ning; Cohen, Joanna S.; Shaknovich, Rita; Vanommeslaeghe, Kenno; Cheng, Huimin; Liang, Dongdong; Cho, Hyo Je; Abbott, Joshua M.; Tam, Wayne; Du, Wei; Leonard, John P.; Elemento, Olivier; Cerchietti, Leandro; Cierpicki, Tomasz; Xue, Fengtian; MacKerell, Alexander D.; Melnick, Ari

doi:10.1172/jci85795

Cited by 148 publications

(280 citation statements)

References 40 publications

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“…FX1 outperformed all previous BCL6 inhibitors in cell-based pharmacodynamic assays, while maintaining specificity for BCL6. The molecule exhibited favorable pharmacokinetics in vivo and lack of toxicity similar to previous generations of BCL6 inhibitors (41). Other small molecules with potential BCL6 binding activity include the natural product Resveratrol (42), which can induce anti-proliferative and anti-inflammatory activities in different types of cancer cells through various mechanisms (Figure 3) (43).…”

Section: Bcl6 Small Molecule Inhibitorsmentioning

confidence: 90%

“…Even though this small molecule was active in animal models, its binding affinity of ~138 µM was lower than the endogenous BBD (~20 µM) (38). A novel in silico -based fragment based screening method, called SILCS (39, 40), was subsequently used to design the most potent BCL6 inhibitor to date, called FX1 (41). FX1 is the first reported inhibitor with higher affinity for the BCL6 BTB domain than the endogenous corepressor proteins (IC50 ~ 4 µM), demonstrating the feasibility of blocking large protein interactions with small molecules (Figure 3) (41).…”

Section: Bcl6 Small Molecule Inhibitorsmentioning

confidence: 99%

“…A novel in silico -based fragment based screening method, called SILCS (39, 40), was subsequently used to design the most potent BCL6 inhibitor to date, called FX1 (41). FX1 is the first reported inhibitor with higher affinity for the BCL6 BTB domain than the endogenous corepressor proteins (IC50 ~ 4 µM), demonstrating the feasibility of blocking large protein interactions with small molecules (Figure 3) (41). SILCS modeling combined with NMR analysis revealed a more favorable orientation of the compound within the lateral groove aromatic pocket.…”

Section: Bcl6 Small Molecule Inhibitorsmentioning

confidence: 99%

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The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target

Cárdenas

Oswald

et al. 2017

Clinical Cancer Research

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BCL6 was initially discovered as an oncogene in B-cell lymphomas, where it drives the malignant phenotype by repressing proliferation and DNA damage checkpoints and blocking B-cell terminal differentiation. BCL6 mediates its effects by binding to hundreds of target genes, and then repressing these genes by recruiting several different chromatin modifying corepressor complexes. Structural characterization of BCL6-corepressor complexes suggested that BCL6 might be a druggable target. Accordingly a number of compounds have been designed to bind to BCL6 and block corepressor recruitment. These compounds, based on peptide or small molecule scaffolds, can potently block BCL6 repression of target genes and kill lymphoma cells. In the case of diffuse large B-cell lymphomas (DLBCLs), BCL6 inhibitors are equally effective in suppressing both the GCB- and the more aggressive ABC-DLBCL subtypes, both of which require BCL6 to maintain their survival. In addition, BCL6 is implicated in an expanding scope of hematologic and solid tumors. These include but are not limited to B-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer and non-small cell lung cancer. BCL6 inhibitors have been shown to exert potent effects against these tumor types. Moreover mechanism based combinations of BCL6 inhibitors with other agents has yielded synergistic and often quite dramatic activity. Hence there is a compelling case to accelerate development of BCL6 targeted therapies for translation to the clinical setting.

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Section: Bcl6 Small Molecule Inhibitorsmentioning

confidence: 90%

Section: Bcl6 Small Molecule Inhibitorsmentioning

confidence: 99%

Section: Bcl6 Small Molecule Inhibitorsmentioning

confidence: 99%

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The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target

Cárdenas

Oswald

et al. 2017

Clinical Cancer Research

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149

172

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“…In addition to GCB lymphomas, it has been shown that gain-of-function in BCL6 frequently occurs in ABC lymphomas (6), which display a more mature, post-germinal center phenotype. The role of BCL6 in ABC lymphomas remains largely unknown and it is possible that its alteration is required only for initiation of this lymphoma subtype (18), although recent reports indicate that activated B-cell lymphomas may require sustained BCL6 activity (19). As above, KMT2D and CREBBP are frequently mutated in follicular lymphoma and DLBCL and have also been implicated in B-cell maturation specifically via a reduction in CD40L and cytokine responsive transcription (8,9,20).…”

Section: Introductionmentioning

confidence: 98%

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT-EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased Bcell maturation and a greater dependence on B-cell activation signaling.

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“…14,15 It is therefore necessary to develop in vitro models that recapitulate in vivo systems while mitigating the biological variability (e.g. 3 dimensionality, tumor-endothelial interactions, etc.)…”

Section: Introductionmentioning

confidence: 99%

3D microvascular model recapitulates the diffuse large B-cell lymphoma tumor microenvironment in vitro

et al. 2017

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Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer that affects ~22,000 people in the United States yearly. Understanding the complex cellular interactions of the tumor microenvironment is critical to the success and development of DLBCL treatment strategies. In vitro platforms that successfully model the complex tumor microenvironment without introducing the variability of in vivo systems are vital for understanding these interactions. To date, no such in vitro model exists that can accurately recapitulate the interactions that occur between immune cells, cancer cells, and endothelial cells in the tumor microenvironment of DLBCL. To that end, we developed a lymphoma-on-chip model consisting of a hydrogel based tumor model traversed by a vascularized, perfusable, round microchannel that successfully recapitulates key complexities and interactions of the in vivo tumor microenvironment in vitro. We have shown that the perfusion capabilities of this technique allow us to study targeted treatment strategies, as well as to model the diffusion of infused reagents spatiotemporally. Furthermore, this model employs a novel fabrication technique that utilizes common laboratory materials, and allows for the microfabrication of multiplex microvascular environments without the need for advanced microfabrication facilities. Through our facile microfabrication process, we are able to achieve micro vessels within a tumor model that are highly reliable and precise over the length of the vessel. Overall, we have developed a tool that enables researchers from many diverse disciplines to study previously inaccessible aspects of the DLBCL tumor microenvironment, with profound implications for drug delivery and design.

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

Cited by 148 publications

References 40 publications

The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target

The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

3D microvascular model recapitulates the diffuse large B-cell lymphoma tumor microenvironment in vitro

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