BLU-782 (Synonyms: Activin Receptor-like Kinase 2 Inhibitor 1, ALK2-IN-1, Fidrisertib) |
| カタログ番号GC19508 |
BLU-782は、ミュータントALK2を選択的に標的とするように特別に設計された経口精密療法である。
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Cas No.: 2141955-96-4
Sample solution is provided at 25 µL, 10mM.
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BLU-782は、ミュータントALK2を選択的に標的とするように特別に設計された経口精密療法である。
FOPは、骨形成タンパク質（BMP）に対する過敏性とアクチビンへの新形態応答を引き起こすALK2遺伝子の変異によって引き起こされる稀な遺伝性障害であり、骨格筋、靱帯、腱が骨に変換されることが特徴である。
BLU-782は、細胞アッセイでR206HミュータントALK2に対して非常に優れた選択性を示したが、ALK1、ALK3、およびALK6などの関連性の高いアンチターゲットをスパーリングしている。さらに、BLU-782は、アクチビンA、アクチビンB、およびBMP6を含む活性化リガンドに関係なく、in vitroでミュータントALK2を強力に阻害した。ALK2R206H遺伝子組み込みマウスモデルにおけるin vivo研究では、マイクロCTおよびMRIによって測定された、傷害誘発性HOおよび浮腫の形成をBLU-782が防いだ。免疫組織化学の解析では、ALK2R206Hマウスにおける組織損傷への健康的な応答の回復、特に骨格筋繊維の再生が示された。さらに、ALK2R206Hマウスにおける脛骨切開手術後の手術誘発性HOの形成もBLU-782が防いだ。
最近完了した健康なボランティアを対象とした第I相臨床試験（NCT03858075）によると、BLU-782は安全性が確立された治験薬であり、半減期は約24時間であり、優れた薬物動態学および薬物動態学の特性を示している。
BLU-782は野生型ALK2に最小限の干渉を与えながら、ミュータントALK2だけを選択的に標的とすることができ、将来のFOP治療の良い戦略となる可能性がある。
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, KÖster 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)
| 動物実験 [1]: | |
動物モデル | ALK2R206H マウス |
準備方法 | WT（野生型）またはALK2R206H マウスに、一方の脚にピンチ傷害を受ける前に予防的にBLU-782を投与した。 |
投与形態 | BLU-782を1日1回、50 mg/kgの用量で19日間投与。 |
アプリケーション | BLU-782はALK2R206H マウスにおいて早期の浮腫を抑制し、HO（骨化性線維性異形成）を予防する。 |
参考文献: | |
| Cas No. | 2141955-96-4 | SDF | |
| 同義語 | Activin Receptor-like Kinase 2 Inhibitor 1, ALK2-IN-1, Fidrisertib | ||
| Chemical Name | 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 | ||
| Formula | C31H42N6O4 | M.Wt | 562.715 |
| 溶解度 | Soluble in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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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 |
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- Purity: >98.00%
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Average Rating: 5 (Based on Reviews and 30 reference(s) in Google Scholar.)
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