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Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-09 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00359 William McCoull 1 , Roman D. Abrams 2 , Erica Anderson 3 , Kevin Blades 2 , Peter Barton 1 , Matthew Box 2 , Jonathan Burgess 2 , Kate Byth 3 , Qing Cao 3 , Claudio Chuaqui 3 , Rodrigo J. Carbajo 1 , Tony Cheung 3 , Erin Code 3 , Andrew D. Ferguson 3 , Shaun Fillery 1 , Nathan O. Fuller 3 , Eric Gangl 3 , Ning Gao 3 , Matthew Grist 2 , David Hargreaves 1 , Martin R. Howard 1 , Jun Hu 3 , Paul D. Kemmitt 1 , Jennifer E. Nelson 2 , Nichole O’Connell 3 , D. Bryan Prince 3 , Piotr Raubo 1 , Philip B. Rawlins 1 , Graeme R. Robb 1 , Junjie Shi 4 , Michael J. Waring 2 , David Whittaker 2 , Marta Wylot 1 , Xiahui Zhu 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-09 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00359 William McCoull 1 , Roman D. Abrams 2 , Erica Anderson 3 , Kevin Blades 2 , Peter Barton 1 , Matthew Box 2 , Jonathan Burgess 2 , Kate Byth 3 , Qing Cao 3 , Claudio Chuaqui 3 , Rodrigo J. Carbajo 1 , Tony Cheung 3 , Erin Code 3 , Andrew D. Ferguson 3 , Shaun Fillery 1 , Nathan O. Fuller 3 , Eric Gangl 3 , Ning Gao 3 , Matthew Grist 2 , David Hargreaves 1 , Martin R. Howard 1 , Jun Hu 3 , Paul D. Kemmitt 1 , Jennifer E. Nelson 2 , Nichole O’Connell 3 , D. Bryan Prince 3 , Piotr Raubo 1 , Philip B. Rawlins 1 , Graeme R. Robb 1 , Junjie Shi 4 , Michael J. Waring 2 , David Whittaker 2 , Marta Wylot 1 , Xiahui Zhu 3
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Inhibition of the protein–protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand–protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.
中文翻译：
吡唑并[1,5- a ]嘧啶B细胞淋巴瘤6（BCL6）粘合剂的发现和对高亲和力大环抑制剂的优化
抑制B细胞淋巴瘤6（BCL6）和共抑制因子之间的蛋白相互作用是在弥漫性大B细胞淋巴瘤（DLBCL）癌症中的治疗目标，有效和选择性BCL6抑制剂的概况分析对于检验该假设至关重要。我们鉴定了吡唑并[1,5- a片段筛选中的] pyrimidine系列BCL6结合物与虚拟筛选平行。使用基于结构的药物设计，结合亲和力增加了100000倍。这包括置换结晶水，形成新的配体-蛋白质相互作用和大环化，以促进配体的生物活性构象。进行了慢速离解速率恒定动力学的优化，并提高了对脱靶激酶CK2的选择性。进一步优化了细胞BCL6分析的效价，以提供高度选择性的探针分子。在许多DLBCL细胞系和多发性骨髓瘤细胞系中仅观察到微弱的抗增殖作用，而与BCL6的效力没有明显的关系。结果，我们得出结论，DLBCL癌症中的BCL6假设仍未得到证实。
更新日期：2017-05-09
中文翻译：
吡唑并[1,5- a ]嘧啶B细胞淋巴瘤6（BCL6）粘合剂的发现和对高亲和力大环抑制剂的优化
抑制B细胞淋巴瘤6（BCL6）和共抑制因子之间的蛋白相互作用是在弥漫性大B细胞淋巴瘤（DLBCL）癌症中的治疗目标，有效和选择性BCL6抑制剂的概况分析对于检验该假设至关重要。我们鉴定了吡唑并[1,5- a片段筛选中的] pyrimidine系列BCL6结合物与虚拟筛选平行。使用基于结构的药物设计，结合亲和力增加了100000倍。这包括置换结晶水，形成新的配体-蛋白质相互作用和大环化，以促进配体的生物活性构象。进行了慢速离解速率恒定动力学的优化，并提高了对脱靶激酶CK2的选择性。进一步优化了细胞BCL6分析的效价，以提供高度选择性的探针分子。在许多DLBCL细胞系和多发性骨髓瘤细胞系中仅观察到微弱的抗增殖作用，而与BCL6的效力没有明显的关系。结果，我们得出结论，DLBCL癌症中的BCL6假设仍未得到证实。
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