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更新于：2025-03-22
AST-3424
更新于：2025-03-22
概要
基本信息
原研机构 |
非在研机构 |
最高研发阶段临床2期 |
首次获批日期- |
最高研发阶段(中国)临床2期 |
特殊审评- |
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结构/序列
分子式C21H25N4O6P |
InChIKeyNWGZZGNICQFUHV-OAHLLOKOSA-N |
CAS号2097713-68-1 |
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7
项与 AST-3424 相关的临床试验CTR20191399
评价AST-3424治疗恶性肿瘤患者的安全性、耐受性、药代动力学、疗效以及与AKR1C3酶表达相关性的临床研究
CTR20201908
评价AST-3424 治疗复发或难治性急性淋巴细胞白血病患者的安全性、耐受性、药代动力学、初步疗效以及疗效与AKR1C3 酶表达相关性的临床研究
NCT04315324
A Phase II Study of AKR1C3-Activated Prodrug OBI-3424 (OBI-3424) in Patients With Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL)
100 项与 AST-3424 相关的临床结果
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100 项与 AST-3424 相关的转化医学
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100 项与 AST-3424 相关的专利（医药）
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9
项与 AST-3424 相关的文献（医药）2025-01-15INTERNATIONAL JOURNAL OF CANCER
Enhanced pharmacological activities of AKR1C3‐activated prodrug AST‐3424 in cancer cells with defective DNA repair
Article
作者: Duan, Jianxin ; Meng, Fanying ; Liu, Xing ; Jung, Don ; Li, Anrong ; Qi, Tianyang ; Wang, Yizhi ; Cai, Xiaohong ; Lu, Zhaoqiang ; Yu, Jibing
Abstract:
AST‐3424 is a novel and highly tumor‐selective prodrug. AST‐3424 is activated by AKR1C3 to release a toxic bis‐alkylating moiety, AST 2660. In this study, we have investigated the essential role of DNA repair in AST‐3424 mediated pharmacological activities in vitro and in vivo. We show here that AST‐3424 is effective as a single therapeutic agent against cancer cells to induce cytotoxicity, DNA damage, apoptosis and cell cycle arrest at G2 phase in a dose‐ and AKR1C3‐dependent manner in both p53‐proficient H460 (RRID:CVCL_0459) and p53‐deficient HT‐29 cells (RRID:CVCL_0320). The combination of abrogators of G2 checkpoint with AST‐3424 was only synergistic in HT‐29 but not in H460 cells. The enhanced activity of AST‐3424 in HT‐29 cells was due to impaired DNA repair ability via the attenuation of cell cycle G2 arrest and reduced RAD51 expression. Furthermore, we utilized a BRCA2 deficient cell line and two PDX models with BRCA deleterious mutations to study the increased activity of AST‐3424. The results showed that AST‐3424 exhibited enhanced in vitro cytotoxicity and superior and durable in vivo anti‐tumor effects in cells deficient of DNA repair protein BRCA2. In summary, we report here that when DNA repair capacity is reduced, the in vitro and in vivo activity of AST‐3424 can be further enhanced, thus providing supporting evidence for the further evaluation of AST‐3424 in the clinic.
2023-08-01British journal of cancer
Phase 1 dose-escalation study evaluating the safety, pharmacokinetics, and clinical activity of OBI-3424 in patients with advanced or metastatic solid tumors.
Article
作者: Hsu, Pei ; Pearce, Tillman E. ; Wesolowski, Robert ; Verschraegen, Claire F. ; Shia, Chi-Sheng ; Tsimberidou, Apostolia Maria
BACKGROUND:
Report of a Phase 1 dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264).
METHODS:
A classic 3 + 3 design was used to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of OBI-3424 administered intravenously, as a single agent, at doses of 1, 2, 4, 6, 8, or 12 mg/m2 (days 1 and 8 of a 21-day cycle, Schedule A) or 8, 10, 12, or 14 mg/m2 (day 1 of a 21-day cycle, Schedule B).
RESULTS:
Dose-limiting hematologic toxicities at 12 mg/m2 in Schedule A led to dose and schedule modifications (Schedule B). In Schedule B, maximum tolerated dose was not reached at the maximum dose tested (14 mg/m2). Grade ≥3 anemia was noted in 3/6 patients treated at 14 mg/m2; the RP2D was 12 mg/m2 (Schedule B). Grade ≥3 treatment-emergent adverse events were experienced by 19/39 (49%) and included anemia (41%) and thrombocytopenia (26%); three patients experienced serious treatment-emergent adverse events (grade ≥3 anemia and thrombocytopenia). One patient had a partial response and 21/33 (64%) had stable disease.
CONCLUSIONS:
The RP2D is 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated; dose-dependent, noncumulative thrombocytopenia and anemia were dose-limiting.
2023-06-01Journal of pharmacological sciences
A novel AKR1C3 specific prodrug AST-3424 and its combination therapy in hepatocellular carcinoma
Article
作者: Qin, Shukui ; Zheng, Xia ; Zhang, Yu ; Xun, Chen
OBJECTIVE:
AST-3424 is a novel specific aldo-keto reductase 1C3 (AKR1C3) prodrug that releases a DNA alkylating reagent upon reduction by AKR1C3. This study aimed to evaluate the efficacy and safety of AST-3424 in patient-derived tumor xenograft (PDTX) model and orthotopic model against hepatocellular carcinoma (HCC).
MATERIALS AND METHOD:
PDTX models derived from three HCC patients and orthotopic mice models using HepG2 cells were developed. The mice were treated with AST-3424 alone or combined with other drugs (oxaliplatin, apatinib, sorafenib and elemene in PDTX models, oxaliplatin and 5- fluorouracil in orthotopic models). The tumor volume and weight, as well as the mice weight were assessed. The liver tumor and transplanted tumor were removed for histological, immunohistochemical and Western blot detection in orthotopic model experiments.
RESULTS:
AST-3424 could inhibit tumor growth in HCC PDTX models and orthotopic models, with no difference in safety compared with other marketed drugs, and the drug combination did not increase toxicity. The inhibitory effect of combination treatment was more obvious than which used alone. The reduction of AKR1C3 expression was negatively correlated with AST-3424 dose.
CONCLUSION:
AST-3424 had a promising effect against HCC in PDTX model and orthotopic model with good safety. It could promote the sensitivity of other drugs without increasing toxicity. Clinical trials are warranted to further certify its antitumor effect and safety.
100 项与 AST-3424 相关的药物交易
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外链
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 急性髓性白血病 | 临床2期 | 中国 |  深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
| 膀胱癌 | 临床2期 | 中国 | 深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
| 结直肠癌 | 临床2期 | 中国 | 深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
| 子宫内膜癌 | 临床2期 | 中国 | 深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
| 食管癌 | 临床2期 | 中国 | 深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
| 结外NK-T细胞淋巴瘤 | 临床2期 | 中国 | 深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
| 肝细胞癌 | 临床2期 | 中国 | 深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
| 高危骨髓增生异常综合征 | 临床2期 | 中国 | 深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
| 非小细胞肺癌 | 临床2期 | 中国 | 深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
| 外周T细胞淋巴瘤 | 临床2期 | 中国 | 深圳艾欣达伟医药科技有限公司初创企业 | 2022-06-23 |
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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 | 晚期恶性实体瘤 AKR1C3 expression | 21 | AST-3424 8 mg/m2 | 範襯壓鹹夢製窪顧構窪(獵獵廠壓築獵選觸選糧) = 築夢觸壓獵簾鬱憲壓鑰 糧鏇夢淵憲鏇觸鹽構鑰 (網憲齋繭獵艱築鑰淵網 ) 更多 | 积极 | 2024-05-24 | |
临床1期 | 39 | 鏇壓鹽膚淵廠蓋鑰壓獵(齋膚製窪簾顧醖淵築淵) = 壓膚網範選糧鏇壓繭鹹 鏇夢壓構壓醖鑰廠顧製 (衊淵簾淵醖糧簾廠構夢 ) | - | 2023-05-12 | |||
临床1/2期 | - | 壓鏇淵鬱艱積夢鏇鏇觸(製餘顧窪鹽餘膚壓淵鬱) = 襯窪膚顧夢繭窪襯鏇廠 鹽蓋構願觸艱構範選壓 (構餘衊廠淵鬱夢遞糧壓 ) | - | 2022-06-15 | |||
Pembrolizumab | 壓鏇淵鬱艱積夢鏇鏇觸(製餘顧窪鹽餘膚壓淵鬱) = 構壓鹽網襯構齋鹹製鹹 鹽蓋構願觸艱構範選壓 (構餘衊廠淵鬱夢遞糧壓 ) | ||||||
临床1期 | 39 | 淵膚積醖鹹壓艱鏇蓋糧(簾顧築廠選鹹範觸製夢) = 簾膚壓襯觸鹽廠繭簾襯 醖窪積觸願網鑰簾鏇遞 (製壓繭繭築衊鹹選廠齋 ) 更多 | - | 2022-06-02 |
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