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Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-10-17 , DOI: 10.1021/acschembio.8b00698 William McCoull 1 , Tony Cheung 2 , Erica Anderson 2 , Peter Barton 1 , Jonathan Burgess 1 , Kate Byth 2 , Qing Cao 2 , M Paola Castaldi 2 , Huawei Chen 2 , Elisabetta Chiarparin 1 , Rodrigo J Carbajo 1 , Erin Code 2 , Suzanna Cowan 1 , Paul R Davey 1 , Andrew D Ferguson 2 , Shaun Fillery 1 , Nathan O Fuller 2 , Ning Gao 2 , David Hargreaves 1 , Martin R Howard 1 , Jun Hu 2 , Aarti Kawatkar 2 , Paul D Kemmitt 1 , Elisabetta Leo 1 , Daniel M Molina 3 , Nichole O'Connell 2 , Philip Petteruti 2 , Timothy Rasmusson 2 , Piotr Raubo 1 , Philip B Rawlins 1 , Piero Ricchiuto 1 , Graeme R Robb 1 , Monica Schenone 4 , Michael J Waring 1 , Michael Zinda 2 , Stephen Fawell 2 , David M Wilson 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-10-17 , DOI: 10.1021/acschembio.8b00698 William McCoull 1 , Tony Cheung 2 , Erica Anderson 2 , Peter Barton 1 , Jonathan Burgess 1 , Kate Byth 2 , Qing Cao 2 , M Paola Castaldi 2 , Huawei Chen 2 , Elisabetta Chiarparin 1 , Rodrigo J Carbajo 1 , Erin Code 2 , Suzanna Cowan 1 , Paul R Davey 1 , Andrew D Ferguson 2 , Shaun Fillery 1 , Nathan O Fuller 2 , Ning Gao 2 , David Hargreaves 1 , Martin R Howard 1 , Jun Hu 2 , Aarti Kawatkar 2 , Paul D Kemmitt 1 , Elisabetta Leo 1 , Daniel M Molina 3 , Nichole O'Connell 2 , Philip Petteruti 2 , Timothy Rasmusson 2 , Piotr Raubo 1 , Philip B Rawlins 1 , Piero Ricchiuto 1 , Graeme R Robb 1 , Monica Schenone 4 , Michael J Waring 1 , Michael Zinda 2 , Stephen Fawell 2 , David M Wilson 1
Affiliation
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B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pull down. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of diffuse large B-cell lymphoma (DLBCL) cell lines, but neither BCL6 inhibition nor degradation selectively induced marked phenotypic response. To investigate, we monitored PROTAC directed BCL6 degradation in DLBCL OCI-Ly1 cells by immunofluorescence and discovered a residual BCL6 population. Analysis of subcellular fractions also showed incomplete BCL6 degradation in all fractions despite having measurable PROTAC concentrations, together providing a rationale for the weak antiproliferative response seen with both BCL6 inhibitor and degrader. In summary, we have developed potent and selective BCL6 inhibitors and a BCL6 PROTAC that effectively degraded BCL6, but both modalities failed to induce a significant phenotypic response in DLBCL despite achieving cellular concentrations.
中文翻译：
新型B细胞淋巴瘤6（BCL6）PROTAC的开发，以深入了解BCL6的小分子靶向。
B细胞淋巴瘤6（BCL6）抑制是治疗血液系统癌症的一种有前途的机制，但是高质量的化学探针对于评估其治疗潜力是必不可少的。在这里，我们报告了有效的BCL6抑制剂，它们可证明细胞靶标参与并在化学蛋白质组学分析后基于质谱分析显示出对BCL6的出色选择性。重要的是，还开发了一种靶向蛋白水解的嵌合体（PROTAC），并显示出它可以在许多弥漫性大B细胞淋巴瘤（DLBCL）细胞系中显着降解BCL6，但BCL6抑制和降解均不能选择性地诱导明显的表型反应。为了研究，我们通过免疫荧光监测了DLBCL OCI-Ly1细胞中PROTAC定向的BCL6降解，并发现了残留的BCL6群体。尽管有可测量的PROTAC浓度，对亚细胞组分的分析也显示了所有组分中BCL6的降解均不完全，这为BCL6抑制剂和降解剂均具有较弱的抗增殖反应提供了理论依据。总而言之，我们已经开发出有效且选择性的BCL6抑制剂和有效降解BCL6的BCL6 PROTAC，但是尽管达到细胞浓度，这两种方式均无法在DLBCL中诱导显着的表型反应。
更新日期：2018-10-17
中文翻译：
新型B细胞淋巴瘤6（BCL6）PROTAC的开发，以深入了解BCL6的小分子靶向。
B细胞淋巴瘤6（BCL6）抑制是治疗血液系统癌症的一种有前途的机制，但是高质量的化学探针对于评估其治疗潜力是必不可少的。在这里，我们报告了有效的BCL6抑制剂，它们可证明细胞靶标参与并在化学蛋白质组学分析后基于质谱分析显示出对BCL6的出色选择性。重要的是，还开发了一种靶向蛋白水解的嵌合体（PROTAC），并显示出它可以在许多弥漫性大B细胞淋巴瘤（DLBCL）细胞系中显着降解BCL6，但BCL6抑制和降解均不能选择性地诱导明显的表型反应。为了研究，我们通过免疫荧光监测了DLBCL OCI-Ly1细胞中PROTAC定向的BCL6降解，并发现了残留的BCL6群体。尽管有可测量的PROTAC浓度，对亚细胞组分的分析也显示了所有组分中BCL6的降解均不完全，这为BCL6抑制剂和降解剂均具有较弱的抗增殖反应提供了理论依据。总而言之，我们已经开发出有效且选择性的BCL6抑制剂和有效降解BCL6的BCL6 PROTAC，但是尽管达到细胞浓度，这两种方式均无法在DLBCL中诱导显着的表型反应。
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