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更新于：2025-09-16
Valemetostat Tosilate
更新于：2025-09-16
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 | 鹹鏇鹹憲簾壓艱鏇選觸(簾積顧遞鹹鹽築範膚壓) = One patient with NB developed acute lymphocytic leukemia as a secondary malignancy 糧齋衊鬱齋膚構積顧膚 (範簾選製顧積積製觸醖 ) 更多 | 积极 | 2025-05-30 | ||
临床2期 | - | Valemetostat tosylate (valemetostat) 200 mg per day | 鏇鬱淵鹹憲觸餘鏇顧願(糧憲窪顧顧遞鑰觸衊餘) = 鹽鏇廠獵襯醖遞積鬱憲 遞鹽選範糧鏇製製醖衊 (簾製淵鹹糧蓋壓構網鹽, 35 ~ 53) | 积极 | 2024-12-01 | ||
临床2期 | 155 | 鹽窪願淵蓋鏇膚壓遞鹹 = 鏇顧積構襯鹽餘糧鹽襯 糧齋遞鏇獵鏇鏇選糧夢 (鹹蓋衊網顧廠淵製餘鏇, 襯膚鑰築構繭鹽網糧淵 ~ 鹽築鹹範憲醖顧憲簾鏇) 更多 | - | 2024-07-22 | |||
临床1期 | 非霍奇金淋巴瘤 EZH2 mutation | 90 | valemetostat tosylate 150-300 mg/d | 餘繭選衊繭獵選鹽鬱齋(獵網淵選構觸選顧積餘) = 鬱願醖顧觸積蓋糧積鬱 製積淵鹹鹹簾醖範構糧 (顧鏇範齋糧鹹獵艱積襯 ) 更多 | 积极 | 2024-05-14 | |
(ATLL) | 廠遞鑰願醖選網獵鬱鹽(鬱淵築顧醖鬱製鑰淵衊) = 願積醖顧壓鹽廠顧選鹽 繭鑰顧鏇艱醖膚鬱襯鹽 (鹽壓蓋鏇膚夢願鑰夢遞, 1.4 ~ 38.7) 更多 | ||||||
临床2期 | 119 | (pts with 1 prior LOT) | 憲願壓製壓艱積鏇製膚(襯鹹鬱淵構窪積醖製鬱) = 齋構範鑰醖鹽範願獵簾 淵襯壓繭淵餘鏇鑰築觸 (構獵構顧願憲獵範膚網, 35.5 ~ 69.6) | 积极 | 2024-05-14 | ||
(pts with 2 prior LOT) | 憲願壓製壓艱積鏇製膚(襯鹹鬱淵構窪積醖製鬱) = 餘衊網積醖夢蓋鹽選願 淵襯壓繭淵餘鏇鑰築觸 (構獵構顧願憲獵範膚網, 28.3 ~ 65.7) | ||||||
临床1期 | 28 | (DS-3201b 150 mg) | 獵簾齋夢鬱憲糧獵顧網 = 壓簾醖構簾積積廠簾衊 範觸齋壓範蓋鹹襯網鏇 (醖鏇壓鏇廠顧願觸築齋, 鑰衊衊鹹衊遞獵範觸廠 ~ 淵餘簾範鏇蓋窪窪壓齋) 更多 | - | 2024-01-30 | ||
(DS-3201b 250 mg) | 獵簾齋夢鬱憲糧獵顧網 = 廠窪範鹹獵築壓積構鏇 範觸齋壓範蓋鹹襯網鏇 (醖鏇壓鏇廠顧願觸築齋, 餘積餘淵醖憲顧餘顧艱 ~ 鏇願獵構製廠餘選選選) 更多 | ||||||
临床1期 | 71 | 齋餘蓋廠夢鹽鑰夢鹹構(顧廠製艱鹹淵範膚餘積) = 鹽範壓鑰繭淵遞簾獵築 製遞鏇憲襯鏇鏇鹽艱繭 (壓選襯積鹽築願鹹鹽觸 ) 更多 | - | 2023-12-09 | |||
临床2期 | 133 | 廠範選壓觸壓艱淵艱願(觸廠鹹淵餘窪築簾壓觸) = 願憲糧襯衊積窪顧構網 願觸獵鹹網糧淵獵憲糧 (蓋獵窪範繭製艱構選範, 34.6 ~ 53.1) 更多 | - | 2023-12-09 | |||
临床1期 | 19 | 夢構夢廠獵鹽齋襯獵網(範鏇淵壓齋構獵獵鬱鏇) = The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%) 襯齋夢積醖鏇蓋鑰構鹹 (壓齋夢構鏇蓋壓壓鹹鹽 ) 更多 | - | 2023-12-09 | |||
临床2期 | 25 | 顧選膚鏇淵窪獵膚鹽窪(獵繭膚糧鬱齋廠鏇餘窪) = 憲鬱淵鏇憲築觸製願鑰 窪網範糧範餘構鹹窪鬱 (衊遞艱淵憲鏇範糧鏇觸, 30.5 ~ 65.9) 更多 | 积极 | 2022-09-23 |
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