Design, synthesis and biological evaluation of a novel spiro oxazolidinedione as potent p300/CBP HAT inhibitor for the treatment of ovarian cancer
Design, synthesis and biological evaluation of a novel spiro oxazolidinedione as potent p300/CBP HAT inhibitor for the treatment of ovarian cancer
复制标题
新型螺恶唑烷二酮作为有效的 p300/CBP HAT 抑制剂用于治疗卵巢癌的设计、合成和生物学评价
DOI：
10.1016/j.bmc.2021.116512
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发表时间：
2021-12-15
影响因子：
3.5
通讯作者：
Yang, Yaxi
中科院分区：
文献类型：
--
作者：
Ding, Hong;Pei, Yuan;Yang, Yaxi
组蛋白乙酰化修饰是表观遗传修饰的重要组成部分之一，介导了多种复杂的生物学功能。在这些过程中，p300/CBP可以催化组蛋白3（H3 K27 ac）上赖氨酸27的乙酰化，并已被报道通过增强染色质转录活性介导多种肿瘤的发生和发展。卵巢癌是一种恶性程度极高的肿瘤，也被观察到发生组蛋白的异常乙酰化。然而，是否可以通过抑制p300/CBP对H3 K27的乙酰化活性来实现卵巢癌的治疗尚未得到很好的研究。本文中，我们对p300/CBP HAT结构域抑制剂A-485进行了结构修饰，获得了一种高活性小分子13 f，其抑制p300体外酶活性的IC 50值为0.49 nM，对卵巢癌细胞系OVCAR-3的抗增殖IC 50值为153 nM。此外，13 f在OVCAR-3异种移植模型中具有较强的乙酰化酶家族选择性、良好的代谢稳定性和有希望的体内抗肿瘤活性。13 f的发现揭示了p300/CBP的HATs结构域的一个更有活性的化学实体，为表观遗传抑制剂在卵巢癌治疗中的应用提供了新的思路。
Histone acetylation is one of the most essential parts of epigenetic modification, mediating a variety of complex biological functions. In these procedure, p300/CBP could catalyze the acetylation of lysine 27 on histone 3 (H3K27ac), and had been reported to mediate tumorigenesis and development in a variety of tumors by enhancing chromatin transcription activity. Ovarian cancer, as an extremely malignant tumor, has also been observed to undergo abnormal acetylation of histones. However, whether the treatment of ovarian cancer could be achieved by inhibiting the acetylation activity of p300/CBP on H3K27 has not been well investigated. In this article, we modified the structure of p300/CBP HAT domain inhibitor A-485 and obtained a highly active small molecule known as 13f, which has an IC50 value of 0.49 nM for inhibiting the in vitro enzyme activity of p300, as well as the anti-proliferation IC50 value on ovarian cancer cell line OVCAR-3 was 153 nM. In addition, 13f had strong acetylase family selectivity, good metabolic stability and promising in vivo anti-tumor activity in OVCAR-3 xenograft model. The discovery of 13f revealed a more active chemical entity of the HATs domain of p300/CBP and provided a novel idea for the application of epigenetic inhibitors in the treatment of ovarian cancer.