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| Product Name: | RapaLink-1 | | Synonyms: | RapaLink-1;RAPALINK 1;RAPALINK1;Rapamycin, 42-O-[2-[[1-[32-[4-amino-3-(2-amino-5-benzoxazolyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-27-oxo-3,6,9,12,15,18,21,24-octaoxa-28-azadotriacont-1-yl]-1H-1,2,3-triazol-4-yl]methoxy]ethyl]-;N-(4-(4-Amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)-1-(4-((2-(((1R,2R,4S)-4-((R)-2-((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-3-yl)propyl)-2-methoxycyclohexyl)oxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12,15,18,21,24-octaoxa;N-(4-(4-Amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)-1-(4-((2-(((1R,2R,4S)-4-((R)-2-((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-3-yl)propyl)-2-methoxycyclohexyl)oxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide;42-O-[2-[[1-[32-[4-Amino-3-(2-amino-5-benzoxazolyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-27-oxo-3,6,9,12,15,18,21,24-octaoxa-28-azadotriacont-1-yl]-1H-1,2,3-triazol-4-yl]methoxy]ethyl]rapamycin | | CAS: | 1887095-82-0 | | MF: | C91H138N12O24 | | MW: | 1784.17 | | EINECS: | | | Product Categories: | chem-chemical;API | | Mol File: | 1887095-82-0.mol |  |
| | RapaLink-1 Chemical Properties |
| density | 1.30±0.1 g/cm3(Predicted) | | storage temp. | Store at -20°C | | solubility | ≥ 178.4mg/mL in DMSO | | form | Solid | | pka | 10.40±0.70(Predicted) | | color | White to light yellow |
| | RapaLink-1 Usage And Synthesis |
| Uses | RapaLink-1, the third-generation bivalent mTOR inhibitor, combines Rapamycin (HY-10219) with MLN0128 (HY-13328, a second-generation mTOR kinase inhibitor) by an inert chemical linker. RapaLink-1 shows better efficacy than Rapamycin or mTOR kinase inhibitors (TORKi), potently blocking cancer-derived, activating mutants of mTOR. RapaLink-1 can cross the blood-brain barrier. RapaLink-1 binding to FKBP12 results in targeted and durable inhibition of mTORC1. RapaLink-1 plays an antithrombotic role in antiphospholipid syndrome by improving autophagy. Anticancer activity[1][2]. | | in vivo | RapaLink-1 (i.p.; every 5 days for 25 days, then once a week for 11 week) shows potent anti-tumor efficacy[1]. | Animal Model: | BALB/ Cnu/nu mice bearing U87MG intracranial xenografts[1] | | Dosage: | 1.5 mg/kg | | Administration: | I.p.; every 5 days for 25 days, then once a week for 11 week | | Result: | Led to initial regression and subsequent stabilization of tumor size.
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| | IC 50 | mTOR | | Background | RapaLink-1 is a small-molecule inhibitor of the mammalian target of rapamycin, a Ser/Thr protein kinase that functions as an ATP and amino acid sensor to balance nutrient availability and cell growth. mTOR inhibitors, such as rapamycin, are used to inhibit the PIK3K-AKT-mTOR pathway, which is a commonly activated pathway in human cancers. RapaLink-1 is an example of a third-generation mTOR inhibitor, which combines the effects of both first-generation and second-generation mTOR inhibitors. Specifically, RapaLink-1 combines the high specificity binding and inhibition of mTORC1 found in rapamycin with the broader specificity of the second-generation mTOR inhibitors, which inhibit both mTORC1 and mTORC2. Several studies have demonstrated that RapaLink-1 can display therapeutic effects in glioblastoma, follicular lymphoma, and renal cell carcinoma, often overcoming resistance to earlier-generation mTOR inhibitors. | | References | [1] Fan Q, et al. A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma. Cancer Cell. 2017 Mar 13;31(3):424-435. DOI:10.1016/j.ccell.2017.01.014
[2] Kuroshima K, et al. Potential new therapy of Rapalink-1, a new generation mammalian target of rapamycin inhibitor, against SU 11248-resistant renal cell carcinoma. Cancer Sci. 2020 May;111(5):1607-1618. DOI:10.1111/cas.14395
[3] Rodrik-Outmezguine VS, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016 Jun 9;534(7606):272-6. DOI:10.1038/nature17963
[4] Mu F, et al. RapaLink-1 plays an antithrombotic role in antiphospholipid syndrome by improving autophagy both in vivo and vitro. Biochem Biophys Res Commun. 2020 Apr 30;525(2):384-391. DOI:10.1016/j.bbrc.2020.02.084 |
| | RapaLink-1 Preparation Products And Raw materials |
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