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Optimization of Ligands Using Focused DNA-Encoded Libraries To Develop a Selective, Cell-Permeable CBX8 Chromodomain Inhibitor.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-12 , DOI: 10.1021/acschembio.9b00654 Sijie Wang 1 , Kyle E Denton 1 , Kathryn F Hobbs 2 , Tyler Weaver 2 , James M B McFarlane 3 , Katelyn E Connelly 1 , Michael C Gignac 3 , Natalia Milosevich 3 , Fraser Hof 3 , Irina Paci 3 , Catherine A Musselman 2 , Emily C Dykhuizen 1 , Casey J Krusemark 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-12 , DOI: 10.1021/acschembio.9b00654 Sijie Wang 1 , Kyle E Denton 1 , Kathryn F Hobbs 2 , Tyler Weaver 2 , James M B McFarlane 3 , Katelyn E Connelly 1 , Michael C Gignac 3 , Natalia Milosevich 3 , Fraser Hof 3 , Irina Paci 3 , Catherine A Musselman 2 , Emily C Dykhuizen 1 , Casey J Krusemark 1
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Polycomb repressive complex 1 (PRC1) is critical for mediating gene expression during development. Five chromobox (CBX) homolog proteins, CBX2, CBX4, CBX6, CBX7, and CBX8, are incorporated into PRC1 complexes, where they mediate targeting to trimethylated lysine 27 of histone H3 (H3K27me3) via the N-terminal chromodomain (ChD). Individual CBX paralogs have been implicated as drug targets in cancer; however, high similarities in sequence and structure among the CBX ChDs provide a major obstacle in developing selective CBX ChD inhibitors. Here we report the selection of small, focused, DNA-encoded libraries (DELs) against multiple homologous ChDs to identify modifications to a parental ligand that confer both selectivity and potency for the ChD of CBX8. This on-DNA, medicinal chemistry approach enabled the development of SW2_110A, a selective, cell-permeable inhibitor of the CBX8 ChD. SW2_110A binds CBX8 ChD with a Kd of 800 nM, with minimal 5-fold selectivity for CBX8 ChD over all other CBX paralogs in vitro. SW2_110A specifically inhibits the association of CBX8 with chromatin in cells and inhibits the proliferation of THP1 leukemia cells driven by the MLL-AF9 translocation. In THP1 cells, SW2_110A treatment results in a significant decrease in the expression of MLL-AF9 target genes, including HOXA9, validating the previously established role for CBX8 in MLL-AF9 transcriptional activation, and defining the ChD as necessary for this function. The success of SW2_110A provides great promise for the development of highly selective and cell-permeable probes for the full CBX family. In addition, the approach taken provides a proof-of-principle demonstration of how DELs can be used iteratively for optimization of both ligand potency and selectivity.
中文翻译：
使用聚焦的DNA编码库优化配体，以开发选择性的，可渗透细胞的CBX8色域抑制剂。
聚梳抑制复合物1（PRC1）对于在发育过程中介导基因表达至关重要。五个色盒（CBX）同源蛋白CBX2，CBX4，CBX6，CBX7和CBX8被整合到PRC1复合物中，它们通过N端染色体结构域（ChD）介导对组蛋白H3（H3K27me3）的三甲基赖氨酸27的靶向作用。个别的CBX旁系同源物已被认为是癌症的药物靶标。然而，CBX ChD之间序列和结构的高度相似性为开发选择性CBX ChD抑制剂提供了主要障碍。在这里，我们报告针对多个同源ChD的小型，集中，DNA编码文库（DEL）的选择，以鉴定对亲本配体的修饰，从而赋予CBX8 ChD选择性和效力。这种基于DNA的药物化学方法使SW2_110A（一种选择性的，CBX8 ChD的细胞可渗透抑制剂。SW2_110A以800 nM的Kd结合CBX8 ChD，在体外对CBX8 ChD的选择性是其他所有CBX同源物的5倍。SW2_110A特异性抑制细胞中CBX8与染色质的缔合，并抑制MLL-AF9易位驱动的THP1白血病细胞的增殖。在THP1细胞中，SW2_110A处理导致MLL-AF9靶基因（包括HOXA9）的表达显着降低，从而验证了CBX8在MLL-AF9转录激活中先前确立的作用，并定义了此功能所必需的ChD。SW2_110A的成功为开发适用于整个CBX系列的高选择性和细胞渗透性探针提供了广阔前景。此外，
更新日期：2019-12-13
中文翻译：
使用聚焦的DNA编码库优化配体，以开发选择性的，可渗透细胞的CBX8色域抑制剂。
聚梳抑制复合物1（PRC1）对于在发育过程中介导基因表达至关重要。五个色盒（CBX）同源蛋白CBX2，CBX4，CBX6，CBX7和CBX8被整合到PRC1复合物中，它们通过N端染色体结构域（ChD）介导对组蛋白H3（H3K27me3）的三甲基赖氨酸27的靶向作用。个别的CBX旁系同源物已被认为是癌症的药物靶标。然而，CBX ChD之间序列和结构的高度相似性为开发选择性CBX ChD抑制剂提供了主要障碍。在这里，我们报告针对多个同源ChD的小型，集中，DNA编码文库（DEL）的选择，以鉴定对亲本配体的修饰，从而赋予CBX8 ChD选择性和效力。这种基于DNA的药物化学方法使SW2_110A（一种选择性的，CBX8 ChD的细胞可渗透抑制剂。SW2_110A以800 nM的Kd结合CBX8 ChD，在体外对CBX8 ChD的选择性是其他所有CBX同源物的5倍。SW2_110A特异性抑制细胞中CBX8与染色质的缔合，并抑制MLL-AF9易位驱动的THP1白血病细胞的增殖。在THP1细胞中，SW2_110A处理导致MLL-AF9靶基因（包括HOXA9）的表达显着降低，从而验证了CBX8在MLL-AF9转录激活中先前确立的作用，并定义了此功能所必需的ChD。SW2_110A的成功为开发适用于整个CBX系列的高选择性和细胞渗透性探针提供了广阔前景。此外，
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