- |||||||||| Review, Journal: B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond. (Pubmed Central) - Oct 26, 2024
Many of these regulatory functions are conserved throughout evolution. The BCL6 gene is also important in human oncology, particularly in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), but also extending to many in other cancers, including a unique role in resistance to a variety of therapies, which collectively make BCL6 inhibitors highly sought-after.
- |||||||||| Journal: Relocalizing transcriptional kinases to activate apoptosis. (Pubmed Central) - Oct 3, 2024
Genomics and proteomics corroborated a gain-of-function mechanism in which global kinase activity was not inhibited but rather redirected. Thus, kinase inhibitors can be used to context-specifically activate transcription.
- |||||||||| Journal: Chemically synthesized osteocalcin alleviates NAFLD via the AMPK-FOXO1/BCL6-CD36 pathway. (Pubmed Central) - Aug 23, 2024
In conclusion, we demonstrated the regulatory role of csOCN in fatty acid uptake pathways for the first time; it regulates CD36 expression via the AMPK-FOXO1/BCL6 axis to reduce fatty acid uptake, and it affects fatty acid transport by may directly binding to CD36. There are indications that csOCN has potential as a CD36-targeted drug for the treatment of NAFLD.
- |||||||||| Epidaza (chidamide) / Chipscreen
Journal: BCL6 confers resistance to HDAC inhibitors in DLBCL. (Pubmed Central) - Aug 17, 2024
Collectively, these findings provided valuable insights into the global impact of chidamide on DLBCL and highlight the potential of targeting HDACs as a therapeutic strategy for DLBCL. Identifying BCL6 as a biomarker for predicting the response to chidamide and the combination therapy with BCL6 inhibition has the potential to lead to more personalized and effective treatments for DLBCL patients.
- |||||||||| The determination of solution phase conformer distribution using NMR data and QM | Poster Board #833 (In-person; Poster Board #833; Hall C (Ernest N. Morial Convention Center)) - Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_12627;
In this work, we present a statistical method in conjunction with NAMFIS, which combines experimental NMR NOE data with QM to improve the predictions of ligand conformer distribution. Application of the aforementioned method to BCL6 inhibitors demonstrates that QM predictions alone misrepresent accessible solution phase conformations.
- |||||||||| BI-3812 / Boehringer Ingelheim
Rewiring EWS/FLI1 with transcriptional chemical inducers of proximity (TCIPs) (Section 21) - Mar 5, 2024 - Abstract #AACR2024AACR_7638;
In our proof-of-concept study we used TCIP1 consisting of ortho-AP1867 (oAP), a synthetic ligand for FKBPF36V, linked to the BCL6 inhibitor BI3812 (BI) to rewire N-FK-E/F...Since ES is driven solely by E/F, TCIPs may be promising next generation therapeutics. Our study provides a proof-of-concept that will be the foundation for the development of future TCIP molecules that recruit endogenous E/F once suitable ligands are developed.
- |||||||||| dexamethasone / Generic mfg.
Preclinical, Journal: Inhibition of Bcl-6 Expression Ameliorates Asthmatic Characteristics in Mice. (Pubmed Central) - Feb 26, 2024
Hence, BCL6 may be a target in treating BPD and neonatal diseases. The amelioration of airway inflammation and airway hyper-responsiveness is achieved through Bcl-6 suppression, which effectively hinders Tfh cell differentiation, ultimately resulting in a concurrent reduction in IgE production.
- |||||||||| Journal, PD(L)-1 Biomarker, IO biomarker: BCL6 promotes a stem-like CD8 T cell program in cancer via antagonizing BLIMP1. (Pubmed Central) - Nov 3, 2023
Prdm1 deficiency also promoted the T cell program and greatly improved the efficacy of anti-PD-1 therapy. Thus, we identified the TGF-?-BCL6 and IL-2-BLIMP1 antagonistic pathways in regulation of antitumor CD8 T cells, which may benefit the development of long-lasting and effective cancer immunotherapy.
- |||||||||| Journal: A small molecule BCL6 inhibitor as chemosensitizers in acute myeloid leukemia. (Pubmed Central) - Sep 18, 2023
We further proved that WK499 and AraC could achieve a better result of inhibiting the growth of AML in vivo. These findings indicate that WK499, a small molecule inhibitor of BCL6, not only inhibits the proliferation of AML, but also provides an effective therapeutic strategy for increasing AML sensitivity to chemotherapy.
- |||||||||| Journal: miR-346 regulates the development of ARDS by regulating the function of pulmonary microvascular endothelial cells. (Pubmed Central) - Aug 25, 2023
BCL6 was predicted to be a target of miR-346 by targetscan and miRDB; when miR-346 was inhibited, BCL6 expression was increased, and if miR-346 and BCL6 expression were inhibited at the same time, it could aggravate lung injury and reduce the proliferation of HPMECs and increase their apoptosis and inflammation in mice. This shows that miR-346 inhibits the migration of HPMECs by regulating BCL6 expression, which in turn promotes the apoptosis of HPMECs, leading to inflammation and inducing ARDS.
- |||||||||| etoposide IV / Generic mfg.
Journal, IO biomarker: Chromosomal Aberration t(14;17)(q32;q21) Simultaneously Activates HOXB5 and miR10a in Triple-Hit B-Cell Lymphoma. (Pubmed Central) - Jun 28, 2023
Functional investigations showed that HOXB5 represses the apoptotic driver BCL2L11 and promotes survival in the presence of etoposide, and that miR10a inhibits BCL6 and may thus play an oncogenic role in later stages of lymphomagenesis. Collectively, we characterize triple-hit B-cell line SC-1 and identify the aberrant expression of HOXB5 and miR10a, both novel oncogenes in B-cell lymphoma.
- |||||||||| Conformation determination using NMR data (Hall F-H (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_2800;
In this work, we present a statistical method in conjunction with NAMFIS, whichcombines experimental NMR NOE data with QM to improve the predictions of ligand conformerdistribution. Application of the aforementioned method to BCL6 inhibitors demonstrates that QMpredictions alone misrepresent accessible solution phase conformations.
- |||||||||| Journal: IL-1β promotes IL-9-producing Th cell differentiation in IL-2-limiting conditions through the inhibition of BCL6. (Pubmed Central) - Nov 18, 2022
IL-1β was unique among NF-kB-activating factors in its ability to rescue Th9 differentiation as IL-2 deprived Th9 cells selectively induced IL-1R expression and IL-1β/IL-1R1 signaling enhanced the sensitivity of Th9 cells to limiting amounts of IL-2 by suppressing expression of the Th9 inhibitory factor BCL6. These data shed new light on the intertwined nature of IL-2 and NF-kB signaling pathways in differentiating Th cells and elucidate the potential mechanisms that promote Th9 inflammatory function in IL-2-limiting conditions.
- |||||||||| Journal: BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer. (Pubmed Central) - Nov 17, 2022
Likewise, pharmacological inhibition of BCL6 significantly impeded the growth of KRAS-mutant lung cancer cells both in vitro and in vivo. In summary, our findings reveal a crucial role of BCL6 in promoting KRAS-addicted lung cancer and suggest BCL6 as a therapeutic target for the treatment of this intractable disease.
- |||||||||| Mekinist (trametinib) / Novartis
BCL6-Mediated Escape from Negative Selection Enables RAS-Driven B-Cell Transformation (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_5946;
We previously investigated targeted engagement of negative selection in B-ALL and showed that hyperactivation of SYK or AKT functionally mimics autoreactive pre-BCR signaling and results in negative selection and cell death (Chen et al., 2015; Shojaee et al., 2016). Here, we reinforced this concept by providing a mechanistic basis on how negative selection is downregulated in RAS-driven B-ALL and how it can be reactivated for therapeutic benefit – namely, BCL6 curbs ERK-mediated induction of PRDM1 expression to promote leukemogenesis and this mechanism can be exploited as synthetic lethality in the treatment of this disease.
- |||||||||| Journal: B-cell lymphoma 6 (BCL6): From master regulator of humoral immunity to oncogenic driver in pediatric cancers. (Pubmed Central) - Sep 29, 2022
Using publicly available data, here we show that BCL6 is ubiquitously overexpressed in pediatric brain tumors, inversely to BCOR, highlighting the potential for targeting BCL6 in these often lethal and untreatable cancers. In this review we summarize what is known of BCL6 (role, effect, mechanisms) in pediatric cancers, highlighting the two sides of BCL6 function, humoral immunity, and tumorigenesis, as well as to review BCL6 inhibitors and highlight areas of opportunity to improve the outcomes of pediatric cancer patients.
- |||||||||| Journal: Balance between immunoregulatory B cells and plasma cells drives pancreatic tumor immunity. (Pubmed Central) - Sep 24, 2022
Transient inhibition of BCL6 in tumor-educated naive B cells is sufficient to reverse the dysfunction in B cell differentiation, stimulating the intra-tumoral accumulation of plasma cells and effector T cells and rendering pancreatic tumors sensitive to anti-programmed cell death protein 1 (PD-1) blockade. Our findings argue that B cell effector dysfunction in cancer can be due to an active systemic suppression program that can be targeted to synergize with T cell-directed immunotherapy.
- |||||||||| Jakafi (ruxolitinib) / Novartis, Incyte
Journal: BCL6 inhibition ameliorates ruxolitinib resistance in CRLF2-rearranged acute lymphoblastic leukemia. (Pubmed Central) - Aug 26, 2022
As a result, FX1 treatment alone had growth-inhibitory and apoptosis-sensitizing effects, but the combination of ruxolitinib and FX1 more potently inhibited leukemia cell growth, enhanced apoptosis sensitivity, and prolonged xenografted mice survival. These findings provide one mechanism for the insufficiency of JAK inhibition for CRLF2-rearranged ALL treatment and BCL6 inhibition as a potentially helpful adjunctive therapy combined with JAK inhibition.
- |||||||||| Conformation determination using NMR data | Poster Board #3364 (Hall F2 (McCormick Place Convention Center)) - Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_3402;
In this work, we present a statistical method in conjunction with NAMFIS, whichcombines experimental NMR NOE data with QM to improve the predictions of ligand conformerdistribution. Application of the aforementioned method to BCL6 inhibitors demonstrates that QMpredictions alone misrepresent accessible solution phase conformations.
- |||||||||| Journal: Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors. (Pubmed Central) - Jun 25, 2022
Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.
- |||||||||| BI-3812 / Boehringer Ingelheim, BI-3802 / Boehringer Ingelheim
Bcl6 Regulates NFκB-Controlled Endothelial Inflammation and Apoptosis (Hynes Room 310) - May 20, 2022 - Abstract #ATC2022ATC_1985;
Our results show that BCL6 regulates NFκB-dependent transcription in endothelium, potentially through chromatin remodeling. We conclude that BCL6 is involved in the initiation, magnitude and termination of inflammation and is implicated in the apoptosis response driven by NFκB in cardiac endothelial cells, and may be a therapeutic target to ameliorate vascular inflammation in transplant rejection.
- |||||||||| etoposide IV / Generic mfg.
Journal: The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress. (Pubmed Central) - May 10, 2022
Accordingly, targeted inhibition of BCL6 remarkably enhanced etoposide-triggered DNA damage and apoptosis both in vitro and in vivo. Our findings highlight the importance of BCL6 signaling in conquering solid tumor tolerance to genotoxic stress, further establishing a rationale for a combined approach with genotoxic agents and BCL6-targeted therapy.
- |||||||||| Journal: Structural basis of Apt48 inhibition of the BCL6 BTB domain. (Pubmed Central) - May 6, 2022
We show that, even with little sequence specificity, the interactions of the lower region are required for the high-affinity binding of the SMRT corepressor and other peptides to the BTB domain. This has relevance for the design of new BCL6 inhibitors and for understanding the evolution of corepressor interactions with the BTB domain.
- |||||||||| Journal: BCL6 and the Notch pathway: a signaling axis leading to a novel druggable biotarget in triple negative breast cancer. (Pubmed Central) - May 3, 2022
This has relevance for the design of new BCL6 inhibitors and for understanding the evolution of corepressor interactions with the BTB domain. Our results may be instrumental for the prospective design of combination treatment strategies that selectively target novel TNBC-associated biomarker(s) whose activity is implicated in the regulation of cancer stemness (such as BCL6) and molecules in developmentally conserved signaling pathways (such as Notch) to achieve long-lasting tumor control and improve patient outcomes.
- |||||||||| Conformation Determination using NMR Data (Virtual Room (Marriott Marquis San Diego Marina)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_1616;
In this work, we present a statistical method in conjunction with NAMFIS, which combines experimental NMR NOE data with QM to improve the predictions of ligand conformer distribution. Application of the aforementioned method to BCL6 inhibitors demonstrates that QM predictions alone misrepresent accessible solution phase conformations.
- |||||||||| Journal: Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket. (Pubmed Central) - Jan 26, 2022
Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.
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