ARV-471
(Synonyms: ARV-471) 目录号 : GC62723
ARV-471 是一种口服生物可利用的雌激素受体靶向（ER靶向）PROTAC, 用于治疗局部晚期或转移性ER+/HER2-乳腺癌患者。
Cas No.:2229711-68-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
Cell lines | MCF7、T47D、T47D ER-Y537S andT47D ER-D538G |
Preparation Method | Five days after ARV-471 treatment of cells, ATP levels were measured using the luminescent Cell-Titer Glo assay to determine cell viability. |
Reaction Conditions | 0.1,1,10,100 and1000 nM, 5 days |
Applications | ARV-471 inhibits the growth of both WT and mutant ER dependent breast cancer cells in-vitro. |
| Animal experiment [1]: | |
Animal models | MCF7 orthotopic xenograft model |
Preparation Method | When the average tumor volume of mice reached 200 mm3, ARV-471 was administered orally once a day for 28 consecutive days. |
Dosage form | 3, 10 and 30 mg/kg/day, 28 days, p.o. |
Applications | ARV-471 displayed dose-dependent tumor growth inhibition at 3, 10 and 30 mg/kg daily, with tumor (volume) inhibition rates of 85%, 98%, and 120%, respectively. |
References: | |
ARV-471 is an orally bioavailable estrogen receptor-targeted (ER-targeted) PROTAC for the treatment of patients with locally advanced or metastatic ER+/HER2- breast cancer[1].
ARV-471 induces degradation of wild-type and mutant ER (≥90%), including MCF-7 cells and ESR1 mutant lines[1]. ARV-471 can inhibit the proliferation of MCF7, T47D, T47D ER-Y537S and T47D ER-D538G cells, with GI50 of 3.3, 4.5, 7.9 and 5.7 nM, respectively[2].
ARV-471 (10 and 30 mpk, 27 days) can inhibit the growth of Patient-Derived tumor Xenograft model with ESR1 mutations and has a good tumor inhibitory effect[1]. ARV-471 (3, 10 and 30 mg/kg, 28 days) dose-dependently inhibited tumor growth in the MCF7 orthotopic xenograft model and promoted ER degradation (≥94%)[2].
References:
[1] Snyder L B, Flanagan J J, Qian Y, et al. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer[J]. Cancer Res, 2021, 81(13): 44.
[2] Gough S M, Flanagan J J, Teh J, et al. Oral estrogen receptor PROTAC® vepdegestrant (ARV-471) is highly efficacious as monotherapy and in combination with CDK4/6 or PI3K/mTOR pathway inhibitors in preclinical ER+ breast cancer models[J]. Clinical Cancer Research, 2024.
ARV-471 是一种口服生物可利用的雌激素受体靶向（ER靶向）PROTAC, 用于治疗局部晚期或转移性ER+/HER2-乳腺癌患者[1]。
ARV-471可诱导野生型和突变型 ER 降解 （≥90%），包括 MCF-7 细胞和 ESR1 突变系[1]。并且ARV-471可抑制 MCF7、T47D、T47D ER-Y537S 和T47D ER-D538G细胞的增殖，GI50分别为3.3、4.5、7.9和5.7nM[2]。
ARV-471（10 and 30 mpk，27 days）可以抑制ESR1 突变的人源肿瘤组织移植瘤模型中肿瘤的生长，具有良好的肿瘤抑制作用[1]。ARV-471（3、10 和 30 mg/kg, 28 days）以剂量依赖性抑制MCF7原位异种移植模型中肿瘤的生长，并且可以促进ER 的降解（≥94%）[2]。
| Cas No. | 2229711-68-4 | SDF | |
| 别名 | ARV-471 | ||
| 分子式 | C45H49N5O4 | 分子量 | 723.9 |
| 溶解度 | DMSO : 110 mg/mL (151.95 mM; Need ultrasonic) | 储存条件 | Store at -20°C, sealed storage, away from moisture and 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 | 1.3814 mL | 6.907 mL | 13.8141 mL |
| 5 mM | 0.2763 mL | 1.3814 mL | 2.7628 mL |
| 10 mM | 0.1381 mL | 0.6907 mL | 1.3814 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。
PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy
Front Pharmacol 2021 May 7;12:692574.PMID:34025443DOI:10.3389/fphar.2021.692574.
Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through the ubiquitin-proteasome system (UPS) to achieve an effect on tumor growth. A number of literature studies on PROTAC technology have proved an insight into the feasibility of PROTAC technology to degrade target proteins. Additionally, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment, which inspires a greater enthusiasm for PROTAC research. Here we focus on the structures and mechanisms of PROTACs and describe several classes of effective PROTAC degraders based on E3 ligases.
Developments of CRBN-based PROTACs as potential therapeutic agents
Eur J Med Chem 2021 Dec 5;225:113749.PMID:34411892DOI:10.1016/j.ejmech.2021.113749.
Protease-targeted chimeras (PROTACs) are a new technology that is receiving much attention in the treatment of diseases. The mechanism is to inhibit protein function by hijacking the ubiquitin E3 ligase for protein degradation. Heterogeneous bifunctional PROTACs contain a ligand for recruiting E3 ligase, a linker, and another ligand to bind to the target protein for degradation. A variety of small-molecule PROTACs (CRBN, VHL, IAPs, MDM2, DCAF15, DCAF16, and RNF114-based PROTACs) have been identified so far. In particular, CRBN-based PROTACs (e.g., ARV-110 and ARV-471) have received more attention for their promising therapeutic intervention. To date, CRBN-based PRTOACs have been extensively explored worldwide and have excelled not only in cancer diseases but also in cardiovascular diseases, immune diseases, neurodegenerative diseases, and viral infections. In this review, we will provide a comprehensive update on the latest research progress in CRBN-based PRTOACs area. Following the criteria, such as disease area and drug target class, we will present the degradants in alphabetical order by target. We also provide our own perspective on the future prospects and potential challenges facing PROTACs.
Overview of PROTACs Targeting the Estrogen Receptor: Achievements for Biological and Drug Discovery
Curr Med Chem 2022;29(22):3922-3944.PMID:34758713DOI:10.2174/0929867328666211110101018.
Estrogen receptors (ERs) are steroid hormone receptors, which belong to a large nuclear receptor family. Endocrine diseases correlate strongly with dysregulated ER signaling. Traditional therapies continue to rely on small molecule inhibitors, including aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs), all of which permit acquired resistance to endocrine therapy. Proteolytic targeting chimeras (PROTACs) offer unprecedented potential for solving acquired endocrine resistance. ARV-471, an ER-targeting PROTAC developed by Arvinas, was designated as an Investigational New Drug by the US FDA in 2019, and a phase I trial in patients suffering from locally advanced or metastatic ER-positive/HER2- negative breast cancer was initiated. In this review, we will focus on progress in developing ER-targeting PROTACs from publications and patents aimed at the treatment of endocrine diseases.
Are we ready to design oral PROTACs®?
ADMET DMPK 2021 Aug 31;9(4):243-254.PMID:35300370DOI:10.5599/admet.1037.
PROTACs® are expected to strongly impact the future of drug discovery. Therefore, in this work we firstly performed a statistical study to highlight the distribution of E3 ligases and POIs collected in PROTAC-DB, the main online database focused on degraders. Moreover, since the emerging technology of protein degradation deals with large and complex chemical structures, the second part of the paper focuses on how to set up a property-based design strategy to obtain oral degraders. For this purpose, we calculated a pool of seven previously ad hoc selected 2D descriptors for the 2258 publicly available degraders in PROTAC-DB (average values: MW= 972.9 Da, nC= 49.5, NAR= 4.5, PHI= 17.3, nHDon= 4.5, nHAcc= 17.7 and TPSA= 240 Å2) and compared them to a dataset of 50 bRo5 orally approved drugs. Then, a chemical space based on nC, PHI and TPSA was built and subregions with optimal permeability and bioavailability were identified. Bioavailable degraders (ARV-110 and ARV-471) tend to be closer to the Ro5 region, using mainly semi-rigid linkers. Permeable degraders, on the other hand, are placed in an average central region of the chemical space but chameleonicity could allow them to be located closer to the two Arvinas compounds.
Advances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery
Bioorg Chem 2022 Aug;125:105848.PMID:35533582DOI:10.1016/j.bioorg.2022.105848.
Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been developed to hijack the ubiquitin-proteasome system (UPS) to induce different POIs degradation. Currently, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging efficacy in clinical trials of prostate and breast cancer treatment, which turns a new avenue for the development of PROTAC research. In this review, we focus on a detailed summary of the latest progress of PROTACs and elucidate the advantages of PROTACs technology. In addition, potential challenges and perspectives of PRTOACs are discussed.