The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target.
The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target.
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DOI：
10.1158/1078-0432.ccr-16-2071
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发表时间：
2017-02-15
期刊：
影响因子：
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通讯作者：
Melnick AM
中科院分区：
文献类型：
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作者：
Cardenas MG;Oswald E;Yu W;Xue F;MacKerell AD Jr;Melnick AM
BCL6最初是作为b细胞淋巴瘤的致癌基因被发现的，它通过抑制增殖和DNA损伤检查点以及阻断b细胞末端分化来驱动恶性表型。BCL6通过结合数百个靶基因来调节其作用，然后通过招募几种不同的染色质修饰辅抑制复合物来抑制这些基因。BCL6-辅抑制复合物的结构表征表明BCL6可能是一个可药物靶点。因此，许多化合物被设计成与BCL6结合并阻断协同抑制因子的募集。这些化合物基于肽或小分子支架，可以有效阻断BCL6对靶基因的抑制并杀死淋巴瘤细胞。在弥漫性大b细胞淋巴瘤（dlbcl）的病例中，BCL6抑制剂在抑制GCB-和更具侵袭性的ABC-DLBCL亚型方面同样有效，这两种亚型都需要BCL6来维持其生存。此外，BCL6与血液和实体肿瘤的范围扩大有关。这些包括但不限于b急性淋巴细胞白血病、慢性髓性白血病、乳腺癌和非小细胞肺癌。BCL6抑制剂已被证明对这些肿瘤类型有强有力的作用。此外，基于机制的BCL6抑制剂与其他药物的联合产生了协同作用，通常具有相当显著的活性。因此，有一个令人信服的案例来加速BCL6靶向治疗的发展，以转化为临床环境。
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.