表观遗传药物：一个崛起的新兴领域

2019年05月30日，Epizyme开发的一款表观遗传药物tazemetostat迎来一个重要里程碑，公司已向FDA递交tazemetostat上市申请，申请加速批准用于转移性/局部晚期上皮样肉瘤，Epizyme将于2019年下半年启动一项全球多中心验证性临床以支持tazemetostat完全批准，同时2019年Q4该药物将会递交滤泡性淋巴瘤适应症的上市申请。

Tazemetostat是一款first-in-class，EZH2抑制剂，表观遗传药物，tazemetostat的未来上市不仅给上皮样肉瘤患者带来创新疗法，而且标志着表观遗传药物的又一次突破。截至目前，已有多款表观遗传药物获批上市，包括HDAC抑制剂，如Zolinza (vorinostat), Beleodaq (belinostat), 爱谱沙 (西达本胺)；Agios Pharmaceuticals开发IDH抑制剂，如Idhifa (enasidenib), Tibsovo (ivosidenib)。

Tazemetostat：first-in-class，EZH2抑制剂

表观遗传药物代表如HDAC抑制剂，IDH抑制剂是一个越来越受关注的抗肿瘤药物开发领域，Tazemetostat的上市将会继续增加表观遗传药物的研发热度！

EZH2 (zeste homolog 2) 被称为组蛋白甲基转移酶，该酶突变或异常激活与细胞异常增殖相关联，EZH2靶点抑制剂能够抑制histone H3 lysine 27 (H3K27)甲基化，从而抑制肿瘤的增长，但是，值得注意的是这里所谓的调控其实非常复杂，这也是这类药物饱受争议、潜在巨大风险的一个重要原因！

Tazemetostat inhibits EZH2-mediated repression of transcription

EZH2, enhancer of zeste homolog 2; INI1, integrase interactor 1; PRC2, polycomb repressive complex 2; SWI/SNF, SWItch/Sucrose Non-Fermentable.

资料来源：Epizyme-ESMO18-Cohort-5-poster

tazemetostat上皮样肉瘤注册临床试验数据：

NCT02601950: A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

ESMO 2018

ASCO 2019，摘要编号11003

tazemetostat开发策略：

着力于3个方向：1.药物联合免疫检查点抑制剂，主要用于DLBCL和NSCLC，2.组合疗法尤其注重DLBCL适应症，3.单药疗法，重点关注DLBCL，FL，INI1阴-实体瘤等。

Pipeline of Epizyme

表观遗传药物：一个崛起的新兴领域

表观遗传药物具有有别于传统的独特的药物作用机制，表观遗传机制复杂，从基因到表型是一个丰富多彩的世界。简单地讲，从基因调控层面着手去开发疾病治疗药物，这是表观遗传药物开发的一个基本思路，例如，很多肿瘤与DNA甲基化、组蛋白修饰、ncRNA等异常相关。

近年，表观遗传药物关注程度越来越受重视，本文所提及的EZH2抑制剂，便是其中一类，其他DNMT抑制剂、HDAC抑制剂及IDH1/2等也相对常见！

Current and emerging epigenetic therapies. Chromatin exists in two major states: an open relaxed conformation called euchromatin, within which most transcriptionally active genes reside, and a more condensed compact state called heterochromatin, which is largely transcriptionally silent. The dynamic transition between these states is mediated by chromatin modifications such as methylation and acetylation, which are laid down by epigenetic writers, bound by epigenetic readers, and removed by epigenetic erasers. Many epigenetic proteins have more than one functional domain, allowing them to function as epigenetic readers and writers or epigenetic readers and erasers. A growing number of smallmolecule drugs are being developed to target these epigenetic regulators. Highlighted in red are the targets for epigenetic therapies that are either in routine clinical use or currently being evaluated in clinical trials. IDH1 and IDH2 are marked with asterisks because although they are not epigenetic proteins, mutations in these proteins profoundly affect epigenetic erasers of DNA methylation (TET proteins) and histone methylation (Jumonji-C domain proteins). Inhibitors of IDH1 and IDH2 reduce levels of the oncometabolite 2HG and alleviate the inhibition of these epigenetic erasers