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摘要: 表观遗传是指在不改变DNA序列的情况下，基因功能产生可遗传的变异，并最终导致生物表型改变的生物学现象。近年来，随着表观遗传与转录等生物过程间的关系不断被揭示，研究者逐渐认识到表观调控异常也是肿瘤发生的原因之一，这为以表观遗传元件为靶点的抗肿瘤药物的研发奠定了基础。目前，在这类药物研发领域内已有多个化合物获批上市，但其临床应用和药物种类仍存在局限性。本文以表观遗传为出发点，对表观遗传抗肿瘤药物研发热点和进展进行介绍，讨论了以编码器、擦除器和阅读器等表观元件为靶点的抑制剂研究现状和临床应用情况。分析当前表观遗传抗肿瘤药物发展的困境，对未来药物临床应用策略和研发趋势进行展望。Abstract: Epigenetics refers to the processes that cellular phenotype is affected by modifications and structural changes in DNA, RNA, and histone, but without changes in DNA sequences. Recently, as functions of epigenetic in some biological processes have been revealed, people gradually recognize that epigenetic dysregulation is closely correlated with tumorigenesis and cancer progression, which provide a solid foundation for the development of anti-tuomor epigenetic drugs. Several epigenetic drugs, including small molecule inhibitors targeting epigenetic regulators like writers, erasers, and readers, have been approved in the past decade. However, problems have emerged in the development of new epigenetic anticancer drugs. For example, drug types and their clinical applications are still limited. In this review, the latest advances in epigenetic antitumor drug development have been introduced and clinical application of promising epigenetic antitumor compound shave been listed. In addition, we also analyze the dilemma and explore future evelopment and application strategies for new epigenetic antitumor drugs.
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Key words:
- epigenetic /
- anti-tumor drug /
- tumor
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表 1 已上市表观抗肿瘤药物
类别 上市药物 适应证 临床试验化合物 DNMT抑制剂 阿扎胞苷 急性髓细胞性白血病、慢性髓细胞白血病、
骨髓增生异常综合征apresoline、prednimustine、hyb101584 地西他滨 HDAC抑制剂 罗米地辛 皮肤T细胞淋巴瘤、外周T细胞淋巴瘤 mocetinostat、entinostat、abexinostat、resminostat、nicotinamide 帕比司他 多发性骨髓瘤 贝利司他 外周T细胞淋巴瘤 伏立诺他 皮肤T细胞淋巴瘤、外周T细胞淋巴瘤 西达本胺 外周T细胞淋巴瘤 EZH2抑制剂 他泽司他 上皮样肉瘤 CPI-1205、SHR2554、PF-06821497、 MAK683 
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表 2 已进入临床试验阶段的BET抑制剂
化合物 临床进展 适应证 PLX51107 Ⅰ 实体瘤、急性髓细胞性白血病、骨髓增生异常综合征、非霍奇金淋巴瘤 FT-1101 Ⅰ 急性髓细胞性白血病、骨髓增生异常综合征、非霍奇金淋巴瘤 ZEN003694 Ⅰ/Ⅱ 三阴性乳腺癌、NUT中线癌、恶性实体瘤、转移性去势抵抗性前列腺癌、卵巢癌、甲状腺滤泡状癌 RO6870810 Ⅰ 急性髓细胞性白血病、骨髓增生异常综合征、多发性骨髓瘤、卵巢癌、三阴性乳腺癌、
弥漫性大B细胞淋巴瘤、高级别B细胞淋巴瘤CPI-0610 Ⅰ/Ⅱ/Ⅲ 外周神经瘤、淋巴瘤、多发性骨髓瘤、实体瘤、皮肤T细胞淋巴瘤 BMS-986158 Ⅰ/Ⅱ 皮肤T细胞淋巴瘤、多发性骨髓瘤、恶性肿瘤、儿童肿瘤 GSK525762 Ⅰ/Ⅱ HR+/HER2-转移性乳腺癌、去势抵抗性前列腺癌、NUT中线癌 NUV-868 Ⅰ/Ⅱ 晚期实体瘤 GSK525762 Ⅰ/Ⅱ 骨髓增生异常综合征、多发性骨髓瘤、急性髓细胞性白血病、皮肤T细胞淋巴瘤、晚期实体瘤 EP31670 I NUT中线癌、去势抵抗性前列腺癌 MK-8628 Ⅰ/Ⅱ NUT中线癌、去势抵抗性前列腺癌、三阴性乳腺癌、非小细胞肺癌、急性髓细胞性白血病、
弥漫性大B细胞淋巴瘤、急性淋巴细胞白血病、多发性骨髓瘤、多形性胶质母细胞瘤AZD5153 Ⅰ 淋巴瘤、卵巢癌、乳腺癌、实体瘤等 SF1126 Ⅰ/Ⅱ 神经母细胞瘤、转移性头颈淋巴细胞癌、晚期肝癌、晚期实体瘤 ABBV-075 Ⅰ 皮肤T细胞淋巴瘤 ABBV-744 Ⅰ 皮肤T细胞淋巴瘤、急性髓细胞性白血病 PLX-2853 Ⅰ/Ⅱ 上皮性卵巢癌、小细胞肺癌、卵巢透明细胞癌、非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、
转移性去势抵抗性前列腺癌、复发/难治性急性髓细胞白血病、高风险骨髓增生异常综合征SYHA1801 Ⅰ 实体瘤 INCB057643 Ⅰ/Ⅱ 实体瘤、皮肤T细胞淋巴瘤、骨髓增生异常综合征 BMS-986158 Ⅰ/Ⅱ 皮肤T细胞淋巴瘤、多发性骨髓瘤、恶性肿瘤、儿童肿瘤 GS-5829 Ⅰ/Ⅱ ER+ HER2-乳腺癌、转移性去势抵抗性前列腺癌、实体瘤、淋巴瘤
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