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GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-21 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00796 F. Anthony Romero 1 , Jeremy Murray 1 , Kwong Wah Lai 2 , Vickie Tsui 1 , Brian K. Albrecht 3 , Le An 1 , Maureen H. Beresini 1 , Gladys de Leon Boenig 1 , Sarah M. Bronner 1 , Emily W. Chan 1 , Kevin X. Chen 2 , Zhongguo Chen 2 , Edna F. Choo 1 , Kyle Clagg 1 , Kevin Clark 1 , Terry D. Crawford 1 , Patrick Cyr 1 , Denise de Almeida Nagata 1 , Karen E. Gascoigne 1 , Jane L. Grogan 1 , Georgia Hatzivassiliou 1 , Wei Huang 2 , Thomas L. Hunsaker 1 , Susan Kaufman 1 , Stefan G. Koenig 1 , Ruina Li 1 , Yingjie Li 2 , Xiaorong Liang 1 , Jiangpeng Liao 2 , Wenfeng Liu 2 , Justin Ly 1 , Jonathan Maher 1 , Colin Masui 1 , Mark Merchant 1 , Yingqing Ran 1 , Alexander M. Taylor 3 , John Wai 2 , Fei Wang 2 , Xiaocang Wei 2 , Dong Yu 2 , Bing-Yan Zhu 1 , Xiaoyu Zhu 2 , Steven Magnuson 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-21 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00796 F. Anthony Romero 1 , Jeremy Murray 1 , Kwong Wah Lai 2 , Vickie Tsui 1 , Brian K. Albrecht 3 , Le An 1 , Maureen H. Beresini 1 , Gladys de Leon Boenig 1 , Sarah M. Bronner 1 , Emily W. Chan 1 , Kevin X. Chen 2 , Zhongguo Chen 2 , Edna F. Choo 1 , Kyle Clagg 1 , Kevin Clark 1 , Terry D. Crawford 1 , Patrick Cyr 1 , Denise de Almeida Nagata 1 , Karen E. Gascoigne 1 , Jane L. Grogan 1 , Georgia Hatzivassiliou 1 , Wei Huang 2 , Thomas L. Hunsaker 1 , Susan Kaufman 1 , Stefan G. Koenig 1 , Ruina Li 1 , Yingjie Li 2 , Xiaorong Liang 1 , Jiangpeng Liao 2 , Wenfeng Liu 2 , Justin Ly 1 , Jonathan Maher 1 , Colin Masui 1 , Mark Merchant 1 , Yingqing Ran 1 , Alexander M. Taylor 3 , John Wai 2 , Fei Wang 2 , Xiaocang Wei 2 , Dong Yu 2 , Bing-Yan Zhu 1 , Xiaoyu Zhu 2 , Steven Magnuson 1
Affiliation
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Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure–activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.
中文翻译：
GNE-781，一种环状磷酸腺苷反应元件结合蛋白，结合蛋白（CBP）的高度有效的选择性溴结构域抑制剂
转录调节因子CBP / P300的溴结构域的抑制是肿瘤学中一种特别有趣的新治疗方法。我们最近公开了CBP溴结构域的体内化学工具1（GNE-272），该工具对BRD4（1）具有中等效力和选择性。为了寻求更有效和更具选择性的CBP抑制剂，我们使用了基于结构的设计。将苯胺1限制为四氢喹啉基序可保持效力，并提高2倍的选择性。结构-活性关系研究以及针对LPF架子，BC环和KAc区域的进一步基于结构的设计使我们能够显着提高效能和选择性，从而鉴定出非CNS渗透剂19（GNE-781，TR-FRET IC 50= 0.94 nM，BRET IC 50 = 6.2 nM；BRD4（1）IC 50 = 5100 nM）在多个物种中保持了良好的体内PK特性。化合物19在AML肿瘤模型中显示抗肿瘤活性，并且还显示以剂量依赖性方式降低Foxp3转录物水平。
更新日期：2017-09-21
中文翻译：
GNE-781，一种环状磷酸腺苷反应元件结合蛋白，结合蛋白（CBP）的高度有效的选择性溴结构域抑制剂
转录调节因子CBP / P300的溴结构域的抑制是肿瘤学中一种特别有趣的新治疗方法。我们最近公开了CBP溴结构域的体内化学工具1（GNE-272），该工具对BRD4（1）具有中等效力和选择性。为了寻求更有效和更具选择性的CBP抑制剂，我们使用了基于结构的设计。将苯胺1限制为四氢喹啉基序可保持效力，并提高2倍的选择性。结构-活性关系研究以及针对LPF架子，BC环和KAc区域的进一步基于结构的设计使我们能够显着提高效能和选择性，从而鉴定出非CNS渗透剂19（GNE-781，TR-FRET IC 50= 0.94 nM，BRET IC 50 = 6.2 nM；BRD4（1）IC 50 = 5100 nM）在多个物种中保持了良好的体内PK特性。化合物19在AML肿瘤模型中显示抗肿瘤活性，并且还显示以剂量依赖性方式降低Foxp3转录物水平。
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