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.
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。
相似文献
1
Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond.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
J Med Chem. 2021 Apr 22;64(8):4333-4358. doi: 10.1021/acs.jmedchem.0c01686. Epub 2021 Apr 12.
2
Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design.通过基于 NMR 的片段筛选和计算机辅助药物设计鉴定 B 细胞淋巴瘤 6 BTB 结构域的硫脲抑制剂。
J Med Chem. 2018 Sep 13;61(17):7573-7588. doi: 10.1021/acs.jmedchem.8b00040. Epub 2018 Jul 17.
3
Discovery of an Irreversible and Cell-Active BCL6 Inhibitor Selectively Targeting Cys53 Located at the Protein-Protein Interaction Interface.发现一种不可逆且具有细胞活性的BCL6抑制剂，其选择性靶向位于蛋白质-蛋白质相互作用界面的Cys53。
Biochemistry. 2018 Feb 27;57(8):1369-1379. doi: 10.1021/acs.biochem.7b00732. Epub 2018 Feb 7.
4
Structural basis of Apt48 inhibition of the BCL6 BTB domain.Apt48 抑制 BCL6 BTB 结构域的结构基础。
Structure. 2022 Mar 3;30(3):396-407.e3. doi: 10.1016/j.str.2021.10.010. Epub 2021 Nov 12.
5
An orally available small molecule BCL6 inhibitor effectively suppresses diffuse large B cell lymphoma cells growth in vitro and in vivo.一种口服小分子 BCL6 抑制剂能有效抑制弥漫性大 B 细胞淋巴瘤细胞的体外和体内生长。
Cancer Lett. 2022 Mar 31;529:100-111. doi: 10.1016/j.canlet.2021.12.035. Epub 2022 Jan 4.
6
GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.GSK137，一种有效的小分子 BCL6 抑制剂，具有体内活性，可抑制小鼠的抗体反应。
J Biol Chem. 2021 Aug;297(2):100928. doi: 10.1016/j.jbc.2021.100928. Epub 2021 Jul 15.
7
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.合理设计的BCL6抑制剂靶向活化B细胞弥漫性大B细胞淋巴瘤。
J Clin Invest. 2016 Sep 1;126(9):3351-62. doi: 10.1172/JCI85795. Epub 2016 Aug 2.
8
9
Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells.特异性肽干扰揭示B细胞淋巴瘤细胞中BCL6的转录和致癌机制。
Nat Med. 2004 Dec;10(12):1329-35. doi: 10.1038/nm1134. Epub 2004 Nov 7.
10
Discovery of a B-Cell Lymphoma 6 Protein-Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach.通过基于生物物理学的片段方法发现一种B细胞淋巴瘤6蛋白-蛋白相互作用抑制剂。
J Med Chem. 2017 May 25;60(10):4358-4368. doi: 10.1021/acs.jmedchem.7b00313. Epub 2017 May 11.
引用本文的文献
1
Advances in pyrazolo[1,5-]pyrimidines: synthesis and their role as protein kinase inhibitors in cancer treatment.吡唑并[1,5 - ]嘧啶的研究进展：合成及其在癌症治疗中作为蛋白激酶抑制剂的作用
RSC Adv. 2025 Feb 5;15(5):3756-3828. doi: 10.1039/d4ra07556k. eCollection 2025 Jan 29.
2
Resveratrol as a BCL6 natural inhibitor suppresses germinal center derived Non-Hodgkin lymphoma cells growth.白藜芦醇作为一种BCL6天然抑制剂可抑制生发中心来源的非霍奇金淋巴瘤细胞生长。
J Nat Med. 2025 Mar;79(2):399-411. doi: 10.1007/s11418-024-01873-4. Epub 2025 Jan 15.
3
B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond.B 细胞淋巴瘤因子 6（BCL6）：免疫调节的保守调控因子及其它功能。
Int J Mol Sci. 2024 Oct 11;25(20):10968. doi: 10.3390/ijms252010968.
4
Immune evasion: An imperative and consequence of MYC deregulation.免疫逃避：MYC 失调的必然结果和影响。
Mol Oncol. 2024 Oct;18(10):2338-2355. doi: 10.1002/1878-0261.13695. Epub 2024 Jul 2.
5
Zinc Finger and BTB Domain-Containing 20: A Newly Emerging Player in Pathogenesis and Development of Human Cancers.锌指和 BTB 结构域蛋白 20：人类癌症发病机制和发展中的新出现的参与者。
Biomolecules. 2024 Feb 4;14(2):192. doi: 10.3390/biom14020192.
6
The N-Terminal Part of CP190 Is a Platform for Interaction with Multiple Architectural Proteins.CP190 的 N 端部分是与多种结构蛋白相互作用的平台。
Int J Mol Sci. 2023 Nov 2;24(21):15917. doi: 10.3390/ijms242115917.
7
Regulates Geese Follicular Selection by Targeting to Regulate Granulosa Cell Proliferation and Apoptosis.通过靶向 来调节颗粒细胞增殖和凋亡，从而调控鹅卵泡选择。
Int J Mol Sci. 2023 Apr 5;24(7):6792. doi: 10.3390/ijms24076792.
8
Discovery of an Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.三环喹啉酮优化发现 BCL6 抑制的新型化学探针。
J Med Chem. 2023 Apr 27;66(8):5892-5906. doi: 10.1021/acs.jmedchem.3c00155. Epub 2023 Apr 7.
9
Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.OICR12694的发现：一种新型、强效、选择性且口服生物可利用的BCL6 BTB结构域抑制剂。
ACS Med Chem Lett. 2023 Jan 12;14(2):199-210. doi: 10.1021/acsmedchemlett.2c00502. eCollection 2023 Feb 9.
10
Analysis of the Correlation of Basic Fibroblast Growth Factor in Serum of Patients with Diffuse Large B-Cell Lymphoma with Clinicopathological Efficacy and International Prognostic Index.分析弥漫大 B 细胞淋巴瘤患者血清中碱性成纤维细胞生长因子与临床病理疗效及国际预后指数的相关性。
Contrast Media Mol Imaging. 2022 Sep 19;2022:8311535. doi: 10.1155/2022/8311535. eCollection 2022.
本文引用的文献
1
BCL6 maintains survival and self-renewal of primary human acute myeloid leukemia cells.BCL6维持原代人类急性髓系白血病细胞的存活和自我更新。
Blood. 2021 Feb 11;137(6):812-825. doi: 10.1182/blood.2019001745.
2
Rationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface.靶向同二聚体界面酪氨酸残基的理性设计共价BCL6抑制剂。
ACS Med Chem Lett. 2020 Apr 3;11(6):1269-1273. doi: 10.1021/acsmedchemlett.0c00111. eCollection 2020 Jun 11.
3
Achieving Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.通过发现和优化苯并咪唑酮 BCL6 降解剂来实现靶蛋白耗竭。
J Med Chem. 2020 Apr 23;63(8):4047-4068. doi: 10.1021/acs.jmedchem.9b02076. Epub 2020 Apr 10.
4
Inducible knock-out of BCL6 in lymphoma cells results in tumor stasis.淋巴瘤细胞中BCL6的诱导性敲除导致肿瘤停滞。
Oncotarget. 2020 Mar 3;11(9):875-890. doi: 10.18632/oncotarget.27506.
5
Synthesis and Biological Evaluation of B-Cell Lymphoma 6 Inhibitors of -Phenyl-4-pyrimidinamine Derivatives Bearing Potent Activities against Tumor Growth.含苯嘧啶胺衍生物的 B 细胞淋巴瘤 6 抑制剂的合成与生物学评价。这些衍生物具有强效的抗肿瘤生长活性。
J Med Chem. 2020 Jan 23;63(2):676-695. doi: 10.1021/acs.jmedchem.9b01618. Epub 2020 Jan 13.
6
Targeted protein degradation: expanding the toolbox.靶向蛋白降解：拓展工具盒。
Nat Rev Drug Discov. 2019 Dec;18(12):949-963. doi: 10.1038/s41573-019-0047-y. Epub 2019 Oct 30.
7
Discovery and optimization of covalent Bcl-xL antagonists.共价 Bcl-xL 拮抗剂的发现和优化。
Bioorg Med Chem Lett. 2019 Dec 1;29(23):126682. doi: 10.1016/j.bmcl.2019.126682. Epub 2019 Sep 13.
8
Drug-Target Association Kinetics in Drug Discovery.药物发现中的药物-靶标结合动力学。
Trends Biochem Sci. 2019 Oct;44(10):861-871. doi: 10.1016/j.tibs.2019.04.004. Epub 2019 May 14.
9
Germinal center-derived lymphomas: The darkest side of humoral immunity.生发中心来源的淋巴瘤：体液免疫的阴暗面。
Immunol Rev. 2019 Mar;288(1):214-239. doi: 10.1111/imr.12755.
10
BCL6 Evolved to Enable Stress Tolerance in Vertebrates and Is Broadly Required by Cancer Cells to Adapt to Stress.BCL6 进化以赋予脊椎动物应激耐受能力，并且广泛被癌细胞用于适应应激。
Cancer Discov. 2019 May;9(5):662-679. doi: 10.1158/2159-8290.CD-17-1444. Epub 2019 Feb 18.
Zotero 插件