Valemetostat

Valemetostat（CAS号1809336-39-7） 是首创的一种选择性 EZH1/2 抑制剂，核心作用靶点为组蛋白甲基转移酶 EZH2（野生型及 Y641、A677、A687 突变型），IC₅₀针对野生型 EZH2 约 1.5 nM，针对突变型 EZH2 为 0.3~0.5 nM，对 EZH1 抑制活性较弱（IC₅₀>10 μM），具有高特异性；临床用于治疗复发 / 难治性滤泡性淋巴瘤，推荐口服剂量为 80 mg / 次、每日 2 次，客观缓解率（ORR）可达 73.3%，且对 EZH2 突变型患者疗效更显著，同时在弥漫性大 B 细胞淋巴瘤中也显示出潜在活性，无明显严重骨髓抑制等毒性。

参考文献：

[1] Dou F, Tian Z, Yang X, Li J, Wang R, Gao J. Valemetostat: First approval as a dual inhibitor of EZH1/2 to treat adult T-cell leukemia/lymphoma. Drug Discov Ther. 2022 Dec 26;16(6):297-299. doi: 10.5582/ddt.2022.01085. Epub 2022 Oct 28. PMID: 36310058.

[2] Maruyama D, Jacobsen E, Porcu P, Allen P, Ishitsuka K, Kusumoto S, Narita T, Tobinai K, Foss F, Tsukasaki K, Feldman T, Imaizumi Y, Izutsu K, Morishima S, Yamauchi N, Yuda J, Brammer JE, Kawamata T, Ruan J, Nosaka K, Utsunomiya A, Wang J, Zain J, Kakurai Y, Yamauchi H, Hizukuri Y, Biserna N, Tachibana M, Inoue A, Horwitz SM. Valemetostat monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: a first-in-human, multicentre, open-label, single-arm, phase 1 study. Lancet Oncol. 2024 Dec;25(12):1589-1601. doi: 10.1016/S1470-2045(24)00502-3. Epub 2024 Oct 29. PMID: 39486432.

[3] Porazzi P, Nason S, Yang Z, Carturan A, Ghilardi G, Guruprasad P, Patel RP, Tan M, Padmanabhan AA, Lemoine J, Fardella E, Zhang Y, Pajarillo R, Chen L, Ugwuanyi O, Markowitz K, Delman D, Angelos MG, Shestova O, Isshiki Y, Blanchard T, Béguelin W, Melnick AM, Linette GP, Beatty GL, Carreno BM, Cohen IJ, Paruzzo L, Schuster SJ, Ruella M. EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models. Cancer Cell. 2025 Mar 10;43(3):537-551.e7. doi: 10.1016/j.ccell.2025.01.013. Epub 2025 Feb 20. PMID: 39983725.