|RapaLink-1游离态|CsnPharm

CAS No.: 1887095-82-0

RapaLink-1 Catalog No. CSN21086

RapaLink-1 is the third-generation mTOR inhibitor exploiting the unique juxtaposition of two drug (first- and second-generation mTOR kinase inhibitors) –binding pockets to create a bivalent interaction that allows inhibition of the mutants which has resistance to the previous TORKi (mTOR kinase inhibitors).

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靶点选择性

生物活性

实验方案

技术信息

生物活性

描述RapaLink-1 is the third-generation mTOR inhibitor which can overcome mTOR resistance mutations. It exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants, and reverses resistance due to mTOR FRB (resistant to Rapamycin) and kinase domain (resistant to AZD8055) mutations. RapaLink-1 is a potent mTOR inhibitor evidenced by suppression of downstream signaling, including p-AKT, p-p70S6K, p-S6 and p-4EBP1, in MCF-7 cells treated with RapaLink-1 at concentration>3nM post 4h. RapaLink-1 at low doses (3–10 nM) was the only drug regimen capable of inhibiting mTOR signalling in both F2108L mTOR- and M2327I mTOR-expressing cells. Administration of 1.5mg/kg RapaLink-1, i.p., weekly, significantly inhibited tumor growth in mice bearing RR1 or TKi-R xenograft tumors^[3]. RapaLink-1 crosses the blood-brain barrier. RapaLink-1 drove regression of intracranial brain cancers in vivo, improving survival compared with earlier-generation inhibitors, first-generation allosteric mTOR inhibitor rapamycin and second-generation TORKi^[4].
作用机制RapaLink-1 is consist of MLN0128 targeting the ATP-site and Rapamycin targeting FRB/FKBP12-site, which facilitates it to exploit the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.^[3]
动物研究
剂量
Mice: 1.5 mg/kg^[1] (i.p.)

给药途径
i.p.
参考文献

动物研究
剂量	Mice: 1.5 mg/kg^[1] (i.p.)
给药途径	i.p.

[1] Rodrik-Outmezguine VS, Okaniwa M, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016 Jun 9;534(7606):272-6.
[2] Fan Q, Aksoy O, et al. A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma. Cancer Cell. 2017 Mar 13;31(3):424-435.
[3] Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A, Won H, Wong W, Berger M, de Stanchina E, Barratt DG, Cosulich S, Klinowska T, Rosen N, Shokat KM. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016 Jun 9;534(7606):272-6. doi: 10.1038/nature17963. Epub 2016 May 18. PMID: 27279227; PMCID: PMC4902179.
[4] Fan Q, Aksoy O, Wong RA, Ilkhanizadeh S, Novotny CJ, Gustafson WC, Truong AY, Cayanan G, Simonds EF, Haas-Kogan D, Phillips JJ, Nicolaides T, Okaniwa M, Shokat KM, Weiss WA. 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. PMID: 28292440; PMCID: PMC5386178.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 0.5605 mL
- 2.8025 mL
- 5.6050 mL
- 5 mM
- 0.1121 mL
- 0.5605 mL
- 1.1210 mL
- 10 mM
- 0.0560 mL
- 0.2802 mL
- 0.5605 mL

技术信息

CAS号	1887095-82-0	储存条件	粉末 Keep in dark place,Inert atmosphere,Store in freezer, under -20°C 液体 -20°C:3-6 月 -80°C:12月
分子式	C91H138N12O24	运输	蓝冰
分子量	1784.14	别名

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