A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo
A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo
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DOI：
10.1182/blood-2008-07-168773
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发表时间：
2009-04-09
期刊：
影响因子：
20.3
通讯作者：
Melnick, Ari
中科院分区：
文献类型：
--
作者：
Cerchietti, Leandro C.;Yang, Shao Ning;Melnick, Ari
BCL6转录抑制因子是弥漫性大B细胞淋巴瘤（DLBCL）中最常涉及的癌基因。BCL6的致淋巴瘤活性取决于其将辅阻遏蛋白募集到其N端BTB结构域上一个独特结合位点的能力。视黄酸和甲状腺激素受体的沉默中介体（SMRT）辅阻遏蛋白的一个重组肽片段可阻断该位点，从而抑制BCL6的生物学功能。将该肽缩短并转化为D - 氨基酸且变为反向构型，以及添加一个融合基序，产生了一种效力更强且更稳定的BCL6抑制剂，它仍然保留了原始SMRT片段的特异性。与L - 肽一样，反向异构BCL6肽抑制剂（RI - BPI）选择性地杀死BCR型而非氧化磷酸化型DLBCL细胞。RI - BPI能够重现BCL6基因缺失小鼠中观察到的生发中心形成失败的情况，并且即使给药长达52周也无毒且无免疫原性。RI - BPI显示出更优的组织穿透持续时间，并因此能够以剂量依赖的方式强力抑制人DLBCL异种移植物的生长。最后，RI - BPI能够杀死原代人DLBCL细胞，但对正常淋巴组织或其他肿瘤没有影响。（《血液》2009年；113卷：3397 - 3405页）
The BCL6 transcriptional repressor is the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCLs). BCL6 lymphomagenic activity is dependent on its ability to recruit corepressor proteins to a unique binding site on its N-terminal BTB domain. A recombinant peptide fragment of the SMRT (silencing mediator for retinoid and thyroid hormone receptor) corepressor that blocks this site can inhibit BCL6 biologic functions. Shortening and conversion of this peptide to D-amino acid and retro configuration as well as the addition of a fusogenic motif yielded a far more potent and stable BCL6 inhibitor that still retained the specificity of the original SMRT fragment. Like the L-peptide, retroinverso BCL6 peptide inhibitor (RI-BPI) selectively killed BCR rather than OxPhos-type DLBCL cells. The RI-BPI could recapitulate the failure to form germinal centers seen in BCL6 null mice yet was nontoxic and nonimmunogenic even when administered for up to 52 weeks. RI-BPI showed superior duration of tissue penetration and could accordingly powerfully suppress the growth of human DLBCLs xenografts in a dose-dependent manner. Finally, RI-BPI could kill primary human DLBCL cells but had no effect on normal lymphoid tissue or other tumors. (Blood. 2009; 113: 3397-3405)