2019年05月30日，Epizyme開發的一款表觀遺傳藥物tazemetostat迎來一個重要裏程碑，公司已向FDA遞交tazemetostat上市申請，申請加速批準用於轉移性/局部晚期上皮樣肉瘤，Epizyme將於2019年下半年啟動一項全球多中心驗證性臨床以支持tazemetostat完全批準，同時2019年Q4該藥物將會遞交濾泡性淋巴瘤適應症的上市申請。
Tazemetostat是一款first-in-class，EZH2抑製劑，表觀遺傳藥物，tazemetostat的未來上市不僅給上皮樣肉瘤患者帶來創新療法，而且標誌著表觀遺傳藥物的又一次突破。截至目前，已有多款表觀遺傳藥物獲批上市，包括HDAC抑製劑，如Zolinza (vorinostat), Beleodaq (belinostat), 愛譜沙 (西達本胺);Agios Pharmaceuticals開發IDH抑製劑，如Idhifa (enasidenib), Tibsovo (ivosidenib)。
Tazemetostat：first-in-class，EZH2抑製劑
表觀遺傳藥物代表如HDAC抑製劑，IDH抑製劑是一個越來越受關注的抗腫瘤藥物開發領域，Tazemetostat的上市將會繼續增加表觀遺傳藥物的研發熱度!
EZH2 (zeste homolog 2) 被稱為組蛋白甲基轉移酶，該酶突變或異常激活與細胞異常增殖相關聯，EZH2靶點抑製劑能夠抑製histone H3 lysine 27 (H3K27)甲基化，從而抑製腫瘤的增長，但是，值得注意的是這裏所謂的調控其實非常複雜，這也是這類藥物飽受爭議、潛在巨大風險的一個重要原因!
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.
資料來源：Epizyme-ESMO18-Cohort-5-poster
tazemetostat上皮樣肉瘤注冊臨床試驗數據：
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，摘要編號11003
tazemetostat開發策略：
著力於3個方向：1.藥物聯合免疫檢查點抑製劑，主要用於DLBCL和NSCLC，2.組合療法尤其注重DLBCL適應症，3.單藥療法，重點關注DLBCL，FL，INI1陰-實體瘤等。
Pipeline of Epizyme
表觀遺傳藥物：一個崛起的新興領域
表觀遺傳藥物具有有別於傳統的獨特的藥物作用機製，表觀遺傳機製複雜，從基因到表型是一個豐富多彩的世界。簡單地講，從基因調控層麵著手去開發疾病治療藥物，這是表觀遺傳藥物開發的一個基本思路，例如，很多腫瘤與DNA甲基化、組蛋白修飾、ncRNA等異常相關。
近年，表觀遺傳藥物關注程度越來越受重視，本文所提及的EZH2抑製劑，便是其中一類，其他DNMT抑製劑、HDAC抑製劑及IDH1/2等也相對常見!
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
鑒於篇幅限製，本文不再展開表觀遺傳藥物的研發進展，整體來講，該領域尚不成熟，筆者也查詢了3篇非常值得讀的文獻綜述，見下表，感興趣讀者可以深入閱讀!
