Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders
Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders
复制标题
通过苯并咪唑酮类BCL6降解物的发现和优化实现体内目标消耗
DOI：
10.1021/acs.jmedchem.9b02076
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发表时间：
2020-04-23
影响因子：
7.3
通讯作者：
Hoelder, Swen
中科院分区：
文献类型：
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作者：
Bellenie, Benjamin R.;Cheung, Kwai-Ming J.;Hoelder, Swen
转录抑制因子BCL 6的失调使得生发中心B细胞的肿瘤发生成为可能，因此BCL 6已被提议作为治疗弥漫性大B细胞淋巴瘤（DLBCL）的治疗靶点。在此，我们报告了一系列苯并咪唑酮抑制剂的BCL 6和它的辅阻遏蛋白之间的蛋白质-蛋白质相互作用的发现。发现这些抑制剂的一个子集会导致BCL 6的快速降解，而药代动力学特性的优化导致了5-的发现（（5-氯-2-（（3R，5S）-4，4-二氟-3，5-二甲基哌啶-1-基）嘧啶-4-基）氨基）-3-（三氟甲基）苯甲酸甲酯（3-羟基-3-甲基丁基）-1-甲基-1，3-二氢-2H-苯并[d]咪唑-2-酮（CCT 369260），经口给药后可降低淋巴瘤异种移植小鼠模型中的BCL 6水平。
Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,SS)-4,4-difluoro-3,5-dimethylpiperi din-1-yl) pyrimidin-4-yl) amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.