Development of Dimethylisoxazole-Attached Imidazo[1,2-a]pyridines as Potent and Selective CBP/P300 Inhibitors,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Development of Dimethylisoxazole-Attached Imidazo[1,2-a]pyridines as Potent and Selective CBP/P300 Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-04-19 , DOI: 10.1021/acs.jmedchem.0c02232
Alex Muthengi ₁ , Virangika K Wimalasena ₂ , Hailemichael O Yosief ₁ , Melissa J Bikowitz _{3,

4} , Logan H Sigua ₂ , Tingjian Wang ₂ , Deyao Li ₂ , Zied Gaieb ₅ , Gagan Dhawan ₆ , Shuai Liu ₁ , Jon Erickson ₁ , Rommie E Amaro ₅ , Ernst Schönbrunn _{3,

4} , Jun Qi _{2,

7} , Wei Zhang ₁

Affiliation

The use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-a]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure–activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound 23, CBP IC₅₀ 72 nM and bromodomain 4, BRD4 IC₅₀ 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains.

中文翻译：

开发二甲基异恶唑连接的咪唑并[1,2-a]吡啶作为强效和选择性 CBP/P300 抑制剂

使用表观遗传溴结构域抑制剂作为抗癌治疗剂已从靶向溴结构域外末端结构域 (BET) 蛋白转变为靶向非 BET 溴结构域。两个最相关的非 BET 溴结构域肿瘤学靶标是环 AMP 反应元件结合蛋白 (CBP) 和 E1A 结合蛋白 P300 (EP300)。为了探索日益增长的 CBP/EP300 兴趣，我们开发了一种高效的二甲基异恶唑连接咪唑的两步合成路线[1,2- a]含吡啶支架的抑制剂。我们高效的两步反应使通过分子建模设计的化合物的高通量合成成为可能，这与结构-活性关系 (SAR) 研究一起促进了对 CBP/EP300 选择性靶向非 BET 溴结构域的总体理解。这导致了一种新的有效和选择性 CBP/EP300 溴结构域抑制剂 UMB298（化合物23，CBP IC ₅₀ 72 nM 和溴结构域 4，BRD4 IC ₅₀ 5193 nM）的鉴定。我们建立的 SAR 与文献报道的 CBP 抑制剂（如 CBP30）非常一致，并证明了利用我们的两步法开发其他溴结构域的抑制剂的优势。

更新日期：2021-05-13

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南