Discovery and optimization of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 bromodomain inhibitors for the treatment of castration-resistant prostate cancer
Discovery and optimization of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 bromodomain inhibitors for the treatment of castration-resistant prostate cancer
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1-(1H-吲哚-1-基)乙酮衍生物作为 CBP/EP300 溴结构域抑制剂的发现和优化，用于治疗去势抵抗性前列腺癌
DOI：
10.1016/j.ejmech.2018.01.087
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发表时间：
2018
影响因子：
6.7
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Xiang Qiuping;Wang Chao;Zhang Yan;Xue Xiaoqian;Song Ming;Zhang Cheng;Li Chenchang;Wu Chun;Li Kuai;Hui Xiaoyan;Zhou Yulai;Smaill Jeff B.;Patterson Adam V.;Wu Donghai;Ding Ke;Xu Yong
CREB(cAMP反应元件结合蛋白)结合蛋白(CBP)及其同系物EP300已成为治疗癌症和炎症性疾病的新靶点。在这里，我们报告了从基于片段的虚拟筛选(FBVS)开始，1-(1H-吲哚-1-基)乙酮衍生物作为CBP/EP300抑制剂的鉴定、优化和评价。缓蚀剂(22E)与CBP络合物的共晶结构为进一步优化提供了坚实的结构基础。最有效的化合物32h与CBP溴结构域结合，在AlphaScreen实验中的IC50值为0.037 μM，是我们手中已报道的CBP溴结构域抑制剂SGC-CBP30的2倍。值得注意的是，化合物32h的酯衍生物(29H)显著抑制了几种前列腺癌细胞系的生长，包括LNCaP、22Rv1和LNCaP衍生的C4-2B。化合物29h抑制LNCaP细胞全长AR(AR-FL)、AR靶基因和其他癌基因的mRNA表达，并降低前列腺癌的生物标志物PSA的表达。CBP/EP300抑制剂29h是一种很有前途的先导化合物，可用于开发抗去势前列腺癌的新疗法。
The CREB (cAMP responsive element binding protein) binding protein (CBP) and its homolog EP300 have emerged as new therapeutic targets for the treatment of cancer and inflammatory diseases. Here we report the identification, optimization and evaluation of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 inhibitors starting from fragment-based virtual screening (FBVS). A cocrystal structure of the inhibitor (22e) in complex with CBP provides a solid structural basis for further optimization. The most potent compound32hbinds to the CBP bromodomain and has an IC50value of 0.037 μM in the AlphaScreen assay which was 2 times more potent than the reported CBP bromodomain inhibitor SGC-CBP30 in our hands.32halso exhibit high selectivity for CBP/EP300 over other bromodomain-containing proteins. Notably, the ester derivative (29h) of compound32hmarkedly inhibits cell growth in several prostate cancer cell lines including LNCaP, 22Rv1 and LNCaP derived C4-2B. Compound29hsuppresses the mRNA expression of full length AR (AR-FL), AR target genes and other oncogene in LNCaP cells.29halso reduces the expression of PSA, the biomarker of prostate cancer. CBP/EP300 inhibitor29hrepresents a promising lead compound for the development of new therapeutics for the treatment of castration-resistant prostate cancer.