BLU-782
(Synonyms: Activin Receptor-like Kinase 2 Inhibitor 1, ALK2-IN-1, Fidrisertib) 目录号 : GC19508
BLU-782 是一种口服精准疗法，专门设计用于选择性靶向突变体 ALK2。
Cas No.:2141955-96-4
Sample solution is provided at 25 µL, 10mM.
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BLU-782 is an oral precision therapy specifically designed to selectively target mutant ALK2[1].
FOP is a rare genetic disorder characterized by the abnormal transformation of skeletal muscle, ligaments and tendons into bone, either spontaneously or as the result of physical trauma. FOP is caused by a mutation in the gene for ALK2, which is known as ACVR1, that causes hypersensitivity to certain bone morphogenetic proteins (BMP) and a neomorphic response to activins[4,5].
BLU-782 demonstrated exquisite selectivity for R206H mutant ALK2 in cellular assays, while sparing closely related anti-targets including ALK1, ALK3, and ALK6. Additionally, BLU-782 potently inhibited mutant ALK2 in vitro, regardless of the activating ligand, including Activin A, Activin B and BMP6. In vivo studies in a conditional knock-in ALK2R206H transgenic mouse model showed BLU-782 prevented the formation of injury-induced HO and edema, as measured by micro computed tomography and magnetic resonance imaging. Immunohistochemistry analyses also showed restoration of a healthy response to tissue injury in ALK2R206H mice, including skeletal myofiber regeneration. In addition, BLU-782 prevented the formation of surgery-induced HO following fibular osteotomy surgery in ALK2R206H mice[1]. BLU-782 dampens edema early and prevents HO in ALK2R206H mice[7].
The Phase I clinical trial BLU-782 in healthy volunteers to establish its safety of the investigational drug was recently completed (NCT03858075), and the result showed that BLU-782 is well tolerated with approximately 24 h of half-life and displays excellent properties of pharmacokinetics and pharmacodynamics[2,3].
Blu-782 selectively targets only mutant ALK2 with minimal interference to wild-type ALK2, which may be a good strategy for future FOP therapy[6].
References:
[1]: Blueprint medicines presents foundational preclinical data supporting the development of BLU-782, a highly selective ALK2 inhibitor, for the treatment of patients with fibrodysplasia ossificans progressive (2018)
[2]: Safety, tolerability, pharmacokinetics, and food effect of BLU-782 in healthy adults (2019). https://clinicaltrials.gov/ct2/show/NCT03858075. Accessed 14 Dec 2021
[3]: Alison DFA, Riadh L, Michael P, Cori AS, Sara G, Faith S, Sean K, Gordon W, Mark H, Robert S, Rachel S, Morgan L, Pauplis R, Vivek K, Andy B, Timothy L (2019) A clinical update on BLU-782, an investigational ALK2 inhibitor in development for fibrodysplasia ossificans progressiva (FOP). https://www.blueprintmedicines.com/wp-content/uploads/2019/09/Blueprint-Medicines-ASBMR-2019-BLU-782-Poster1.pdf.
[4]: Towler OW, Shore EM. BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP). Dev Dyn. 2022 Jan;251(1):164-177. doi: 10.1002/dvdy.387. Epub 2021 Jun 26. PMID: 34133058; PMCID: PMC9068236.
[5]: Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai P, Fastnacht-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, K?ster B, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Morhart R, Mundlos S, Groppe J, Shore EM. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009 Mar;30(3):379-90. doi: 10.1002/humu.20868. PMID: 19085907; PMCID: PMC2921861.
[6]: Meng, X., Wang, H. & Hao, J. Recent progress in drug development for fibrodysplasia ossificans progressiva. Mol Cell Biochem 477, 2327-2334 (2022). https://doi.org/10.1007/s11010-022-04446-9
[7]: A clinical update on BLU-782, an investigational ALK2 inhibitor in development for fibrodysplasia ossificans progressiva (FOP)
BLU-782 是一种口服精准疗法，专门设计用于选择性靶向突变体 ALK2[1]。
FOP 是一种罕见的遗传性疾病，其特征是骨骼肌、韧带和肌腱异常转化为骨骼，这可能是自发的，也可能是身体外伤的结果。 FOP 是由 ALK2（称为 ACVR1）基因突变引起的，它会导致对某些骨形态发生蛋白 (BMP) 的超敏反应和对激活素的新形态反应[4,5]。
BLU-782 在细胞测定中表现出对 R206H 突变体 ALK2 的精妙选择性，同时保留了密切相关的抗靶标，包括 ALK1、ALK3 和 ALK6。此外，BLU-782 在体外有效抑制突变体 ALK2，无论激活配体如何，包括激活素 A、激活素 B 和 BMP6。条件性敲入 ALK2R206H 转基因小鼠模型的体内研究表明，通过微计算机断层扫描和磁共振成像测量，BLU-782 可防止损伤诱导的过氧化氢和水肿的形成。免疫组织化学分析还显示 ALK2R206H 小鼠恢复了对组织损伤的健康反应，包括骨骼肌纤维再生。此外，BLU-782 可防止 ALK2R206H 小鼠腓骨截骨手术后手术诱导的 HO 的形成[1]。 BLU-782 在 ALK2R206H 小鼠中早期抑制水肿并预防 HO[7]。
BLU-782 在健康志愿者中确定其研究药物安全性的 I 期临床试验最近完成 (NCT03858075)，结果表明 BLU-782 具有良好的耐受性，半衰期约为 24 小时，显示优异的药代动力学和药效学特性[2,3].
Blu-782 选择性地仅靶向突变体 ALK2，对野生型 ALK2 的干扰最小，这可能是未来 FOP 治疗的良好策略[6]。
| Animal experiment [1]: | |
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Animal models |
ALK2R206H mice |
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Preparation Method |
WT or ALK2R206H mice were untreated or dosed prophylactically with BLU-782 before receiving a pinch injury to one leg. |
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Dosage form |
50 mpk QD BLU-782 for 19days |
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Applications |
BLU-782 dampens edema early and prevents HO in ALK2R206H mice. |
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References: [1]. A clinical update on BLU-782, an investigational ALK2 inhibitor in development for fibrodysplasia ossificans progressiva (FOP). |
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| Cas No. | 2141955-96-4 | SDF | |
| 别名 | Activin Receptor-like Kinase 2 Inhibitor 1, ALK2-IN-1, Fidrisertib | ||
| 化学名 | 1-Piperazinecarboxylic acid, 4-[6-[5-[4-ethoxy-1-(1-methylethyl)-4-piperidinyl]-2-pyridinyl]pyrrolo[1,2-b]pyridazin-4-yl]-, (3R)-tetrahydro-3-furanyl ester | ||
| Canonical SMILES | O=C(N1CCN(C2=CC=NN3C2=CC(C4=NC=C(C5(OCC)CCN(C(C)C)CC5)C=C4)=C3)CC1)O[C@H]6COCC6 | ||
| 分子式 | C31H42N6O4 | 分子量 | 562.715 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| 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 | 1.7771 mL | 8.8855 mL | 17.771 mL |
| 5 mM | 0.3554 mL | 1.7771 mL | 3.5542 mL |
| 10 mM | 0.1777 mL | 0.8885 mL | 1.7771 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。
Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet