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Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2018-04-21
Xiaoqian Xue, Yan Zhang, Chao Wang, Maofeng Zhang, Qiuping Xiang, Junjian Wang, Anhui Wang, Chenchang Li, Cheng Zhang, Lingjiao Zou, Rui Wang, Shuang Wu, Yongzhi Lu, Hongwu Chen, Ke Ding, Guohui Li, Yong Xu

The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4 (1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target genes PSA in prostate cancer cells at the mRNA level. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.



中文翻译:

含苯并恶嗪酮的3,5-二甲基异恶唑衍生物作为BET溴结构域抑制剂,用于治疗去势抵抗性前列腺癌

溴结构域和末端外蛋白(BET)已成为治疗去势抵抗性前列腺癌(CRPC)的有希望的治疗靶标。我们报告设计,合成和评估的一系列新的含苯并恶嗪酮的3,5-二甲基异恶唑衍生物作为选择性BET抑制剂。一种新的化合物,(R)-12(Y02234),具有结合到BRD4(1)ķ d为110nm的值和溴基结构域块和与IC乙酰赖氨酸相互作用50为100nM值。它也对非BET溴结构域蛋白表现出BET选择性,并在诸如22Rv1和C4-2B的前列腺癌细胞系中显示出合理的抗增殖和集落形成抑制作用。BRD4抑制剂(R)-12它还在mRNA水平上显着抑制ERGMycAR靶标基因PSA在前列腺癌细胞中的表达。(R)-12处理可在22Rv1衍生的异种移植模型中显着抑制前列腺癌的肿瘤生长(TGI = 70%)。这些数据表明,化合物(R)-12是用于开发用于治疗CRPC的新型疗法的有前途的先导化合物。

更新日期:2018-04-25
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