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
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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.