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更新于：2025-10-09
Valemetostat Tosilate
更新于：2025-10-09
概要
基本信息
药物类型 小分子化药 |
别名 valemetostat tosilate、valemetostat tosylate、DS-3201 + [5] |
作用方式 抑制剂 |
作用机制 EZH1抑制剂(Zeste基因增强子同源物1抑制剂)、EZH2抑制剂(组蛋白赖氨酸甲基化酶EZH2抑制剂)、表观遗传学药物 |
在研适应症 |
非在研机构- |
最高研发阶段批准上市 |
首次获批日期 日本 (2022-09-26), |
最高研发阶段(中国)临床1/2期 |
特殊审评孤儿药 (美国)、孤儿药 (欧盟)、孤儿药 (日本) |
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结构/序列
分子式C33H42ClN3O7S |
InChIKeyJSBKGJUYSLVFPF-WJQUPPJOSA-N |
CAS号1809336-93-3 |
关联
21
项与 Valemetostat Tosilate 相关的临床试验NCT06294548
A Phase Ib/II, Dose Escalation and Dose Expansion Study of Valemetostat Tosylate (DS-3201b) With Atezolizumab and Bevacizumab in Advanced Hepatocellular Carcinoma (HCC)
NCT05879484
A Phase Ib/II Multicenter Study of Front Line Pembrolizumab and Valemetostat in PD-L1 Positive, HPV-Negative Recurrent/Metastatic Squamous Cell Carcinoma (SCC) of the Head and Neck: The PANTHERAS
NCT06632977
PREcision DIagnostics in Prostate Cancer Treatment (PREDICT)
100 项与 Valemetostat Tosilate 相关的临床结果
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100 项与 Valemetostat Tosilate 相关的转化医学
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100 项与 Valemetostat Tosilate 相关的专利（医药）
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61
项与 Valemetostat Tosilate 相关的文献（医药）2025-12-01FUNCTIONAL & INTEGRATIVE GENOMICS
Polycomb repressive complex 2 (PRC2) pathway’s role in cancer cell plasticity and drug resistance
Review
作者: Tabari, Mohammad Amin Khazeei ; Khan, Haroon ; Javan, Alireza ; Larsen, Danaé S ; Rezaee, Aryan ; Heidari, Mohammad Mahdi ; Sanaye, Pantea Majma ; Hadipour, Mahboube ; Goleij, Pouya ; Daglia, Maria
Polycomb Repressive Complex 2 (PRC2) is a central regulator of gene expression via the trimethylation of histone H3 on lysine 27. This epigenetic modification plays a crucial role in maintaining cell identity and controlling differentiation, while its dysregulation is closely linked to cancer progression. PRC2 silences tumor suppressor genes, promoting cell proliferation, metastasis, epithelial-mesenchymal transition, and cancer stem cell plasticity. Enhancement of zeste homolog 2 (EZH2) overexpression or gain-of-function mutations have been observed in several cancers, including lymphoma, breast, and prostate cancers, driving aggressive tumor behavior and drug resistance. In addition to EZH2, other PRC2 components, such as embryonic ectoderm development (EED) and suppressor of zeste 12, are essential for complex stability and function. EED, in particular, enhances EZH2 activity and has emerged as a therapeutic target. Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components. PRC2's role extends beyond gene repression, as it contributes to metabolic reprogramming in tumors, regulating glycolysis and lipid synthesis to fuel cancer growth. Furthermore, PRC2 is implicated in chemoresistance, particularly by modulating DNA damage response and immune evasion. Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their use in combination with standard chemotherapy or immunotherapy has great potential for improving patient outcomes in cancers driven by PRC2 dysregulation.
2025-12-01CANCER CHEMOTHERAPY AND PHARMACOLOGY
Pharmacokinetics, metabolism, and excretion of [14C]-valemetostat in healthy male participants, and in vitro plasma protein binding
Article
作者: Siebers, Nicholas ; Inaba, Shinichi ; Craveiro, Thuy Vu ; Ikeda, Tomoko ; Kazui, Miho ; Shimizu, Takako ; Tachibana, Masaya ; Abutarif, Malaz A
INTRODUCTION:
Valemetostat tosylate (valemetostat) is an oral, selective, dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1. This article reports findings on the mass balance and pharmacokinetics of valemetostat in a phase I study; valemetostat metabolite identification in plasma, urine, and fecal samples; and plasma-protein-binding of valemetostat in vitro.
METHODS:
Eight healthy participants received a single 200-mg oral dose of [14C]-valemetostat under fasting conditions. Blood, urine, and feces samples were collected to determine total radioactivity and/or unchanged valemetostat, and for metabolite identification. The binding of valemetostat 600-10,000 ng/mL to plasma, 4% human serum albumin (HSA), and 0.1% alpha-1-acid glycoprotein (AAG) was assessed in vitro.
RESULTS:
Mean cumulative recovery of administered radioactivity was 95.3% by 360 h post-dose, with a mean recovery of 15.6% in urine and 79.8% in feces. Valemetostat accounted for the most radioactivity in the excreta, at 10% and 64.9% of the administered dose in the urine and feces, respectively. CALZ-1809a was the most abundant metabolite, present in all biological samples, and accounted for 5.6% of total radioactivity in the feces. Valemetostat was minimally associated with red blood cells, with a blood-to-plasma total radioactivity ratio of 0.54. In vitro, valemetostat was highly plasma-bound (> 94%) at clinically relevant concentrations, with a higher affinity to AAG than to HSA.
CONCLUSION:
Valemetostat was rapidly absorbed into the systemic circulation, mainly excreted via the biliary/fecal route, primarily metabolized by CYP3A enzymes to CALZ-1809a, and highly bound to plasma proteins, with a greater affinity to AAG than HSA in vitro.
2025-08-01Clinical Pharmacology in Drug Development
Effect of Mild to Moderate Hepatic Impairment on Valemetostat Pharmacokinetics: An Open‐Label, Phase I Study
Article
作者: Tao, Ben ; Oberstein, Samuel ; Craveiro, Thuy Vu ; Lau, Yvonne ; Shimizu, Takako ; Atiee, George J. ; Tachibana, Masaya ; Marbury, Thomas C. ; Abutarif, Malaz A.
Abstract:
Valemetostat tosylate (valemetostat) is a dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1, approved in Japan for the treatment of relapsed/refractory peripheral T‐cell lymphoma and adult T‐cell leukemia/lymphoma. This Phase I, open‐label study evaluated the pharmacokinetics and safety of a single 50‐mg oral dose of valemetostat in participants with hepatic impairment (HI). In total, 24 participants were enrolled into 3 cohorts of mild HI (n = 8) and moderate HI (n = 8) according to the National Cancer Institute's Organ Dysfunction Working Group criteria, and matched healthy participants with normal hepatic function (HF; n = 8). In participants with mild and moderate HI, total valemetostat (bound + unbound) area under the concentration‐time curve extrapolated to infinity was 23% lower (geometric mean ratio [GMR], 77.2% [90% confidence interval (CI), 44.0‐135]) and 35% lower, (GMR, 64.8% [90% CI, 40.6‐103]), respectively, and unbound valemetostat was 19% lower (GMR, 81.1% [90% CI, 47.4‐139]) and 15% higher (GMR, 115% [90% CI, 75.5‐176]), than in participants with normal HF. No treatment‐related adverse events were reported. Based on the result of this trial, no dosing adjustments are recommended for patients with mild to moderate HI receiving valemetostat.
100 项与 Valemetostat Tosilate 相关的药物交易
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研发状态
批准上市
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| 适应症 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|
| 成人T细胞白血病/淋巴瘤 | 日本 | 2022-09-26 | |
| 外周T细胞淋巴瘤 | 日本 | 2022-09-26 |
未上市
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 转移性非小细胞肺癌 | 临床2期 | 美国 | 2024-10-30 | |
| 转移性非小细胞肺癌 | 临床2期 | 中国 | 2024-10-30 | |
| 转移性非小细胞肺癌 | 临床2期 | 日本 | 2024-10-30 | |
| 转移性非小细胞肺癌 | 临床2期 | 阿根廷 | 2024-10-30 | |
| 转移性非小细胞肺癌 | 临床2期 | 巴西 | 2024-10-30 | |
| 转移性非小细胞肺癌 | 临床2期 | 韩国 | 2024-10-30 | |
| 鳞状非小细胞肺癌 | 临床2期 | 美国 | 2024-10-30 | |
| 鳞状非小细胞肺癌 | 临床2期 | 中国 | 2024-10-30 | |
| 鳞状非小细胞肺癌 | 临床2期 | 日本 | 2024-10-30 | |
| 鳞状非小细胞肺癌 | 临床2期 | 阿根廷 | 2024-10-30 |
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临床结果
临床结果
适应症
分期
评价
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临床1期 | 实体瘤 INI1-negative | 30 | 獵壓獵顧齋夢膚鬱壓鏇(鑰遞膚願鬱膚簾壓艱淵) = One patient with NB developed acute lymphocytic leukemia as a secondary malignancy 廠艱範膚遞蓋遞艱壓醖 (壓窪壓築膚鏇願遞鬱願 ) 更多 | 积极 | 2025-05-30 | ||
临床2期 | - | Valemetostat tosylate (valemetostat) 200 mg per day | 鹹觸構積蓋遞構顧構鹽(鏇築壓鏇憲糧憲廠願遞) = 選糧衊窪膚鹽選願製蓋 遞範網齋選鏇鏇艱壓積 (壓網齋餘窪窪壓餘餘壓, 35 ~ 53) | 积极 | 2024-12-01 | ||
临床2期 | 155 | 製網醖艱壓積遞鹽簾蓋 = 鹽鬱糧繭製艱夢齋窪廠 淵憲襯積膚憲窪顧觸積 (膚構築鏇鏇製繭襯窪鑰, 積鏇觸積範窪鹹窪餘窪 ~ 簾網鏇鹽壓獵鬱遞範齋) 更多 | - | 2024-07-22 | |||
临床2期 | 119 | (pts with 1 prior LOT) | 醖壓築顧願齋廠窪憲鹹(鑰範繭獵構憲積選艱願) = 遞願鹹憲廠顧願鹹鑰憲 糧簾繭齋範餘簾觸窪遞 (鹽網醖夢築觸範膚選餘, 35.5 ~ 69.6) | 积极 | 2024-05-14 | ||
(pts with 2 prior LOT) | 醖壓築顧願齋廠窪憲鹹(鑰範繭獵構憲積選艱願) = 糧齋膚淵壓醖憲艱範膚 糧簾繭齋範餘簾觸窪遞 (鹽網醖夢築觸範膚選餘, 28.3 ~ 65.7) | ||||||
临床1期 | 非霍奇金淋巴瘤 EZH2 mutation | 90 | valemetostat tosylate 150-300 mg/d | 淵顧選構窪蓋夢簾網餘(憲構顧顧願選鏇襯醖憲) = 壓憲衊醖積膚繭鏇構製 鬱夢壓壓襯衊糧壓築選 (齋鹹膚鏇築鬱廠鹹鑰築 ) 更多 | 积极 | 2024-05-14 | |
(ATLL) | 餘觸鏇膚積鑰繭夢蓋製(網構願鬱憲襯蓋膚築鏇) = 鑰選鬱願築遞窪壓鹹網 繭鑰築觸衊鏇襯範鏇醖 (糧鹽築鏇範窪願壓蓋鏇, 1.4 ~ 38.7) 更多 | ||||||
临床1期 | 28 | (DS-3201b 150 mg) | 簾糧範簾醖醖鏇蓋繭願 = 艱網範鹹廠製網顧鑰築 鑰蓋襯淵憲廠壓簾鏇構 (餘觸壓鑰鹽製積衊廠糧, 淵繭鏇鑰網範壓壓願鑰 ~ 鑰選餘餘襯鏇襯齋餘鬱) 更多 | - | 2024-01-30 | ||
(DS-3201b 250 mg) | 簾糧範簾醖醖鏇蓋繭願 = 願衊淵築鹹願範築鹹繭 鑰蓋襯淵憲廠壓簾鏇構 (餘觸壓鑰鹽製積衊廠糧, 觸壓築鹽選衊鹽窪齋齋 ~ 夢憲鏇顧廠鹹顧製鏇憲) 更多 | ||||||
临床1期 | 71 | 蓋艱顧築積構願遞獵顧(願繭遞窪繭蓋艱網願願) = 蓋製鹹膚餘獵範願艱築 顧鏇鑰衊製選選鏇選襯 (製齋餘齋鹽鑰範餘鬱範 ) 更多 | - | 2023-12-09 | |||
临床2期 | 133 | 餘製壓範衊壓鬱膚壓餘(構簾網觸窪積蓋繭淵壓) = 簾憲積積製願築簾艱願 觸範築顧顧膚簾醖醖願 (簾簾醖構憲製襯衊簾鹽, 34.6 ~ 53.1) 更多 | - | 2023-12-09 | |||
临床1期 | 19 | 積醖繭獵壓築夢網淵餘(選觸膚選餘簾鏇齋鑰憲) = The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%) 齋獵觸繭艱夢蓋製築鏇 (艱鹹廠憲憲築構鬱醖夢 ) 更多 | - | 2023-12-09 | |||
临床2期 | 25 | 齋鑰遞網壓鹽獵糧窪糧(築蓋築繭醖廠襯獵憲遞) = 範網選蓋遞醖範膚廠夢 範製糧襯繭蓋淵齋壓鑰 (網鏇醖淵網築網艱憲鹹, 30.5 ~ 65.9) 更多 | 积极 | 2022-09-23 |
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