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BCL-6 抑制因子在弥漫性大 B 细胞淋巴瘤治疗中的研究进展及其它进展

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

机构信息

Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201, United States.

Department of Hematology and Oncology, Weill Cornell Medical College, New York, New York 10021, United States.

出版信息

J Med Chem. 2021 Apr 22;64(8):4333-4358. doi: 10.1021/acs.jmedchem.0c01686. Epub 2021 Apr 12.

DOI:10.1021/acs.jmedchem.0c01686
PMID:33844535
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8168288/
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) 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 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 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 are highlighted. Also, the and assays used for the evaluation of new compounds will be discussed.

摘要

B 细胞淋巴瘤 6（BCL6）是生发中心形成的主要调节因子，生发中心产生分泌抗体的浆细胞和记忆 B 细胞，以维持持续的免疫应答。BCL6 的 BTB 结构域（BCL6）形成同源二聚体，通过招募其共抑制蛋白形成具有生物学功能的转录复合物来介导转录抑制。BCL6 与其共抑制蛋白之间的蛋白-蛋白相互作用（PPI）已成为治疗弥漫性大 B 细胞淋巴瘤（DLBCL）和其他一些人类癌症的治疗靶点。本文概述了近年来开发 BCL6 抑制剂的进展，包括可逆抑制剂、不可逆抑制剂和 BCL6 降解剂。将提供抑制剂设计和药物化学策略，用于开发新型化合物。突出显示了新抑制剂与 BCL6 的结合模式。此外，还将讨论用于评估新化合物的和 assays。

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