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Discovery and optimization of novel N-benzyl-3,6-dimethylbenzo[d]isoxazol-5-amine derivatives as potent and selective TRIM24 bromodomain inhibitors with potential anti-cancer activities.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2019-11-09 , DOI: 10.1016/j.bioorg.2019.103424 Qingqing Hu 1 , Chao Wang 1 , Qiuping Xiang 1 , Rui Wang 2 , Cheng Zhang 2 , Maofeng Zhang 3 , Xiaoqian Xue 4 , Guolong Luo 2 , Xiaomin Liu 2 , Xishan Wu 2 , Yan Zhang 1 , Donghai Wu 5 , Yong Xu 6
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2019-11-09 , DOI: 10.1016/j.bioorg.2019.103424 Qingqing Hu 1 , Chao Wang 1 , Qiuping Xiang 1 , Rui Wang 2 , Cheng Zhang 2 , Maofeng Zhang 3 , Xiaoqian Xue 4 , Guolong Luo 2 , Xiaomin Liu 2 , Xishan Wu 2 , Yan Zhang 1 , Donghai Wu 5 , Yong Xu 6
Affiliation
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Tripartite motif-containing protein 24 (TRIM24), recognized as an epigenetic reader for acetylated H3K23 (H3K23ac) via its bromodomain, has been closely involved in tumorigenesis or tumor progression of several cancers. Developing inhibitors of TRIM24 is significant for functional studies and drug discovery. Herein, we report the identification, optimization and evaluation of N-benzyl-3,6-dimethylbenzo[d]isoxazol-5-amines as TRIM24 bromodomain inhibitors starting from an in house library screening. Structure-based optimization leads to two potent and selective compounds 11d and 11h in an Alphascreen assay with IC50 values of 1.88 μM and 2.53 μM, respectively. The viability assay demonstrates the great potential of this series of compounds as inhibitors of proliferation of prostate cancer (PC) cells LNCaP, C4-2B. A colony formation assay further supports this inhibitory activity. Compounds 11d and 11h inhibit cell proliferation of other cancer types such as non-small cell lung cancer (NSCLC) cells A549 with IC50 values of 1.08 μM and 0.75 μM, respectively. These data suggests that compounds 11d and 11h are promising lead compounds for further research.
中文翻译：
发现和优化新型N-苄基-3,6-二甲基苯并[d]异恶唑-5-胺衍生物作为具有潜在抗癌活性的有效和选择性TRIM24溴结构域抑制剂。
包含三方基序的蛋白质24（TRIM24），通过其溴结构域被认为是乙酰化H3K23（H3K23ac）的表观遗传阅读器，与几种癌症的发生或发展密切相关。开发TRIM24抑制剂对于功能研究和药物发现具有重要意义。在这里，我们报告从内部库筛选开始，鉴定，优化和评估N-苄基-3,6-二甲基苯并[d]异恶唑-5-胺作为TRIM24溴结构域抑制剂。基于结构的优化在Alphascreen分析中产生了两种有效的选择性化合物11d和11h，IC50值分别为1.88μM和2.53μM。生存力测定证明该系列化合物作为前列腺癌（PC）细胞LNCaP，C4-2B增殖抑制剂的巨大潜力。菌落形成试验进一步支持了这种抑制活性。化合物11d和11h抑制其他癌症类型的细胞增殖，例如非小细胞肺癌（NSCLC）细胞A549，其IC50值分别为1.08μM和0.75μM。这些数据表明化合物11d和11h是有前途的有前途的化合物，有待进一步研究。
更新日期：2019-11-11
中文翻译：
发现和优化新型N-苄基-3,6-二甲基苯并[d]异恶唑-5-胺衍生物作为具有潜在抗癌活性的有效和选择性TRIM24溴结构域抑制剂。
包含三方基序的蛋白质24（TRIM24），通过其溴结构域被认为是乙酰化H3K23（H3K23ac）的表观遗传阅读器，与几种癌症的发生或发展密切相关。开发TRIM24抑制剂对于功能研究和药物发现具有重要意义。在这里，我们报告从内部库筛选开始，鉴定，优化和评估N-苄基-3,6-二甲基苯并[d]异恶唑-5-胺作为TRIM24溴结构域抑制剂。基于结构的优化在Alphascreen分析中产生了两种有效的选择性化合物11d和11h，IC50值分别为1.88μM和2.53μM。生存力测定证明该系列化合物作为前列腺癌（PC）细胞LNCaP，C4-2B增殖抑制剂的巨大潜力。菌落形成试验进一步支持了这种抑制活性。化合物11d和11h抑制其他癌症类型的细胞增殖，例如非小细胞肺癌（NSCLC）细胞A549，其IC50值分别为1.08μM和0.75μM。这些数据表明化合物11d和11h是有前途的有前途的化合物，有待进一步研究。
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