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Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond.

ABSTRACT: B-cell lymphoma 6 (BCL6) is a master regulator of germinal center formation that produce antibody-secreting plasma cells and memory B-cells for sustained immune responses. The BTB domain of BCL6 (BCL6^BTB) forms a homodimer that mediates transcriptional repression by recruiting its corepressor proteins to form a biologically functional transcriptional complex. The protein-protein interaction (PPI) between the BCL6^BTB and its corepressors has emerged as a therapeutic target for the treatment of DLBCL and a number of other human cancers. This Perspective provides an overview of recent advances in the development of BCL6^BTB inhibitors from reversible inhibitors, irreversible inhibitors, to BCL6 degraders. Inhibitor design and medicinal chemistry strategies for the development of novel compounds will be provided. The binding mode of new inhibitors to BCL6^BTB are highlighted. Also, the in vitro and in vivo assays used for the evaluation of new compounds will be discussed.

SUBMITTER: Ai Y

PROVIDER: S-EPMC8168288 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond.

Ai Yong Y Hwang Lucia L MacKerell Alexander D AD Melnick Ari A Xue Fengtian F

Journal of medicinal chemistry 20210412 8

B-cell lymphoma 6 (BCL6) is a master regulator of germinal center formation that produce antibody-secreting plasma cells and memory B-cells for sustained immune responses. The BTB domain of BCL6 (BCL6<sup>BTB</sup>) forms a homodimer that mediates transcriptional repression by recruiting its corepressor proteins to form a biologically functional transcriptional complex. The protein-protein interaction (PPI) between the BCL6<sup>BTB</sup> and its corepressors has emerged as a therapeutic target f ...[more]

PMID: 33844535

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Project description:BackgroundPopulation-based studies previously showed an improvement in overall survival (OS) for patients with diffuse large B-cell lymphoma (DLBCL) who received chemoimmunotherapy with rituximab. However, there is limited data (especially at the population level) that show a similar trend in OS improvement, in the most recent time period. We hypothesized that survival for DLBCL patients diagnosed in the United States has continued to improve in recent years and intended to measure outcome improvements.MethodsUsing the SEER-18 registries, we compared the incidence and relative survival rates (RSRs) of DLBCL patients between 2002-2007 and 2008-2013 (availability of novel agents, broader use of autologous hematopoietic cell transplantation and improvement in supportive care). Multivariable Cox regression models were used to assess associations between the year of diagnosis and OS while controlling for age, gender, stage, and ethnicity.ResultsThere were a total of 53 439 patients with DLBCL who were diagnosed between 2002 and 2013. Of these, 25 810 were diagnosed during time period-1 and 27 629 diagnosed during time period-2. There was a slight decline in incidence of DLBCL (time period-1 vs time period-2), 7.75 (95% CI = 7.66-7.84) vs 7.43 (95% CI = 7.34-7.52) cases per 100 000 persons, respectively (P < .0001). Overall, there was a modest improvement in DLBCL RSRs, with 5-year RSR improving from 61% (time period-1) to 64% (time period-2) and the improvement was noted across all subsets of patients. On multivariable analysis, patients diagnosed in time period-2 had lower mortality relative to time period-1 (HR = 0.87, 95% CI = 0.85-0.89).ConclusionsOur study shows an improvement in the outcomes of DLBCL patients beyond the introduction of rituximab, although the magnitude of improvement is small. It will be interesting to see the impact of chimeric antigen receptor-T cell therapy translating to population-level survival in the next 5 years.

Dataset Information

Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond.

Publications

Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond.

Similar Datasets

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