Exatecan (DX-8951)
(Synonyms: 依喜替康; DX-8951) 目录号 : GC33108
Exatecan (DX-8951) is a nonprodrug camptothecin (CPT) derivative, exhibits significant topoisomerase I inhibition.
Cas No.:171335-80-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
32 malignant cell lines |
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Preparation Method |
Thus 500-20,000 cells/well in 150 u1 of medium were plated in 96-well flat-bottomed microplates and grown for 24h (P388, CCRF-CEM and K562 cells for 4h), the Exatecan (DX-8951) (in 50 µl medium/well), or the medium alone as a control was added, and the cells were cultured for an additional 3 days. Then calculated Growth inhibition of 50% (GI50) . |
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Reaction Conditions |
Different concentrations for 24 h |
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Applications |
Exatecan (DX-8951) showed strong antiproliferating activity,and the mean GI50 values against breast cancers colon cancers, stomach cancers, and lung cancers were 2.02 ng/ml, 2.92 ng/ml, 1.53 ng/ml, and 0.877 ng/ml respectively. |
| Animal experiment [2]: | |
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Animal models |
Male 6-week-old BALB/c-nu/nu nude mice |
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Preparation Method |
The human tumor lines inoculated s.c. into nude mice and maintained as solid tumors. Various human tumors maintained in nude mice were excised and |
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Dosage form |
50 mg/kg, i.v. |
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Applications |
The q4d×4 schedule more readily caused the regressive effects of Exatecan (DX-8951) compared with the q7d×3, and a schedule of q4d×3 more frequently permitted regrowth of tumors than did the q4d×4 schedule. |
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References: [1]: Mitsui I, Kumazawa E, Hirota Y, Aonuma M, Sugimori M, Ohsuki S, Uoto K, Ejima A, Terasawa H, Sato K. A new water‐soluble camptothecin derivative, DX‐8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Japanese journal of cancer research. 1995 Aug;86(8):776-82. |
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Exatecan (DX-8951) is a nonprodrug camptothecin (CPT) derivative, exhibits significant topoisomerase I inhibition [1]. Exatecan (DX-8951) inhibited topoisomerase I with IC50 of 2.2 μM (0.975 μg/ml) [2].
Exatecan (DX-8951) and SN-38 inhibited topoisomerase activity with IC50 values of 0.82 and 2.3 μg/mL, respectively, topoisomerase I was obtained from SUIT-2 cells [3]. Exatecan (DX-8951)(20 ng/ml) induced DNA fragmentation. In an extract from treated SUIT-2 cells, about 60% of DNA was fragmented at the Exatecan (DX-8951) concentration of 20 ng/ml. Exatecan (DX-8951)(0.05 μg/ml, 24 h ) induced the specific features of apoptosis, namely chromatin condensation, nuclear fragmentation and cytoplasmic vacuolation were apparent in SUIT-2 cells [3].
Exatecan (DX-8951) has shown activity in vivo against a wide range of human tumor xenografts in nude mice, including gastric, pancreatic, colon, breast, ovary, and lung tumors [4]. Exatecan (DX-8951) suppressed the growth of human gastric adenocarcinoma SC-6 xenografted into nude mice. When mice were treated i.v. with Exatecan (DX-8951) three times at 4-day intervals, significant inhibition of tumor growth was observed over a wide dose range (3.325 mg/kg to 50 mg/kg of total dose) without toxic death. Its antitumor activity was dependent on the total dose, and at the highest dose of 50 mg/kg, the tumor growth inhibition rate was 92% [2].
References:
[1]. Kumazawa E, Jimbo T, Ochi Y, et al. Potent and broad antitumor effects of DX-8951f, a water-soluble camptothecin derivative, against various human tumors xenografted in nude mice[J]. Cancer chemotherapy and pharmacology, 1998, 42(3): 210-220.
[2]. Mitsui I, Kumazawa E, Hirota Y, Aonuma M, Sugimori M, Ohsuki S, Uoto K, Ejima A, Terasawa H, Sato K. A new water‐soluble camptothecin derivative, DX‐8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Japanese journal of cancer research. 1995 Aug;86(8):776-82.
[3]. Takiguchi S, Kumazawa E, Shimazoe T, Tohgo A, Kono A. Antitumor effect of DX‐8951, a novel camptothecin analog, on human pancreatic tumor cells and their CPT‐11‐resistant variants cultured in vitro and xenografted into nude mice. Japanese journal of cancer research. 1997 Aug;88(8):760-9.
[4]. De Jager R, Cheverton P, Tamanoi K, et al. DX‐8951f: summary of Phase I clinical trials[J]. Annals of the New York Academy of Sciences, 2000, 922(1): 260-273.
Exatecan (DX-8951) 是一种非前药喜树碱 (CPT) 衍生物，具有显着的拓扑异构酶 I 抑制作用[1]。 Exatecan (DX-8951) 抑制拓扑异构酶 I，IC50 为 2.2 μM (0.975 μg/ml) [2]。
Exatecan (DX-8951) 和 SN-38 抑制拓扑异构酶活性，IC50 值分别为 0.82 和 2.3 μg/mL，拓扑异构酶 I 是从 SUIT-2 细胞中获得的[3]。 Exatecan (DX-8951)(20 ng/ml) 诱导 DNA 断裂。在来自处理过的 SUIT-2 细胞的提取物中，约 60% 的 DNA 在 Exatecan (DX-8951) 浓度为 20 ng/ml 时发生片段化。 Exatecan (DX-8951)(0.05 μg/ml, 24 h )诱导细胞凋亡的特异性特征，即在SUIT-2细胞中染色质浓缩、核碎裂和细胞质空泡化明显[3].< /p>\n
Exatecan (DX-8951) 已在体内显示出对裸鼠体内多种人类肿瘤异种移植物的活性，包括胃癌、胰腺癌、结肠癌、乳腺癌、卵巢癌和肺癌[4] . Exatecan (DX-8951) 抑制异种移植到裸鼠体内的人胃腺癌 SC-6 的生长。当小鼠接受静脉注射治疗时Exatecan (DX-8951) 以 4 天为间隔 3 次，在宽剂量范围（3.325 mg/kg 至 50 mg/kg 总剂量）内观察到肿瘤生长显着抑制，且无毒性死亡。其抗肿瘤活性与总剂量有关，在最高剂量50 mg/kg时，肿瘤生长抑制率为92%[2]。
| Cas No. | 171335-80-1 | SDF | |
| 别名 | 依喜替康; DX-8951 | ||
| Canonical SMILES | O=C1[C@](O)(CC)C2=C(CO1)C(N3CC4=C5C6=C(CC[C@@H]5N)C(C)=C(F)C=C6N=C4C3=C2)=O | ||
| 分子式 | C24H22FN3O4 | 分子量 | 435.45 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C,protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2965 mL | 11.4824 mL | 22.9647 mL |
| 5 mM | 0.4593 mL | 2.2965 mL | 4.5929 mL |
| 10 mM | 0.2296 mL | 1.1482 mL | 2.2965 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer
Clin Breast Cancer 2021 Jun;21(3):e212-e219.PMID:32917537DOI:10.1016/j.clbc.2020.08.006.
The development of antibody-drug conjugates composed of a cytotoxic agent and a monoclonal antibody carrier offers an important alternative to classic chemotherapy strategies. Trastuzumab deruxtecan (DS-8201a) is a next-generation antibody-drug conjugate composed of a monoclonal anti-HER2 antibody and a topoisomerase I inhibitor, an Exatecan derivative (DX-8951f). DS-8201a resulted in favorable outcomes in HER2-positive heavily pretreated breast cancer patients and also had a promising efficacy in patients with HER2-negative/low-expressing disease, whose options are limited. Interestingly, a recently published phase 2 trial (NCT03248492) reported 60% overall response and 97% disease control in patients with HER2-positive disease previously treated with multiple regimens, including trastuzumab emtansine. On the basis of recent clinical trials, the US Food and Drug Administration granted accelerated approval to DS-8201a in advanced or unresectable HER2-positive breast cancer pretreated with at least two HER2-targeting treatment lines. We review all preclinical and clinical data of DS-8201a regarding breast cancer.
A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model
Mol Cancer Ther 2018 Jul;17(7):1494-1503.PMID:29703841DOI:10.1158/1535-7163.MCT-17-0749.
Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor Exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system-activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only rechallenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd upregulated CD86 expression on bone marrow-derived dendritic cells (DC) in vitro and that DS-8201a increased tumor-infiltrating DCs and upregulated their CD86 expression in vivo DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti-PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of rechallenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti-PD-1 antibody, possibly due to increased T-cell activity and upregulated PD-L1 expression induced by DS-8201a. Mol Cancer Ther; 17(7); 1494-503. ©2018 AACR.
Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity
Cancer Sci 2016 Jul;107(7):1039-46.PMID:27166974DOI:10.1111/cas.12966.
Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, Exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not. Furthermore, it was confirmed that DS-8201a was not effective against MDA-MB-468-Luc tumors inoculated at the opposite side of the NCI-N87 tumor, suggesting that the bystander killing effect of DS-8201a is observed only in cells neighboring HER2-positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS-8201a has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T-DM1.
TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor
Mol Cancer Ther 2022 Jul 5;21(7):1090-1102.PMID:35439320DOI:10.1158/1535-7163.MCT-21-1000.
Exatecan and deruxtecan are antineoplastic camptothecin derivatives in development as tumor-targeted-delivery warheads in various formulations including peptides, liposomes, polyethylene glycol nanoparticles, and antibody-drug conjugates. Here, we report the molecular pharmacology of Exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of Exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors. Modeling Exatecan binding at the interface of a TOP1 cleavage complex suggests two novel molecular interactions with the flanking DNA base and the TOP1 residue N352, in addition to the three known interactions of camptothecins with the TOP1 residues R364, D533, and N722. Accordingly, Exatecan showed much stronger TOP1 trapping, higher DNA damage, and apoptotic cell death than the classical TOP1 inhibitors used clinically. We demonstrate the value of SLFN11 expression and homologous recombination (HR) deficiency (HRD) as predictive biomarkers of response to Exatecan. We also show that Exatecan kills cancer cells synergistically with the clinical ATR inhibitor ceralasertib (AZD6738). To establish the translational potential of this combination, we tested CBX-12, a clinically developed pH-sensitive peptide-exatecan conjugate that selectively targets cancer cells and is currently in clinical trials. The combination of CBX-12 with ceralasertib significantly suppressed tumor growth in mouse xenografts. Collectively, our results demonstrate the potency of Exatecan as a TOP1 inhibitor and its clinical potential in combination with ATR inhibitors, using SLFN11 and HRD as predictive biomarkers.
Novel antibody drug conjugates containing Exatecan derivative-based cytotoxic payloads
Bioorg Med Chem Lett 2016 Mar 15;26(6):1542-1545.PMID:26898815DOI:10.1016/j.bmcl.2016.02.020.
Trastuzumab conjugates consisting of Exatecan derivatives were prepared and their biological activities and physicochemical properties were evaluated. The ADCs showed strong efficacy and a low aggregation rate. The Exatecan derivatives were covalently connected via a peptidyl spacer (Gly-Gly-Phe-Gly), which is assumed to be stable in circulation, and were cleaved by lysosomal enzymes following ADC internalization into tumor tissue. These anti-HER2 ADCs exhibited a high potency, specifically against HER2-positive cancer cell lines in vitro. The ADCs, bearing Exatecan derivatives which have more than two methylene chains, exhibited superior cytotoxicity. It was speculated that steric hindrance of the cleavable amide moiety could be involved in the drug release. The adequate alkyl lengths of Exatecan derivatives (13, 14, 15) were from two to four in terms of aggregation rate. The ADC having a hydrophilic moiety showed good efficacy in a HER2-positive and Trastuzumab-resistant breast carcinoma cell model in mice.