RapaLink-1 is the third-generationmTOR inhibitor exploiting the unique juxtaposition of two drug (first- and second-generationmTOR 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).
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]
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