RapaLink-1

RapaLink-1, the third-generation bivalent mTOR inhibitor, combines Rapamycin with MLN0128 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 In Vitro RapaLink-1 (0-200 nM; 3 days) shows U87MG cells growth inhibition. RapaLink-1 (0-12.5 nM; 48 hours) arrests U87MG cells at G0/G1. RapaLink-1 selectively inhibits p-RPS6 S235/236 and p-4EBP1 T37/46 at doses as low as 1.56 nM. Rapalink-1 (100 nM; 24 to 96 hours) suppressed renal cell carcinoma (RCC) cell proliferation by inducing apoptosis and cell cycle arrest. RapaLink-1 exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction. RapaLink-1 overcomes resistance to existing first- and second-generation inhibitors. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Proliferation AssayCell Line: U87MG cells Concentration: 0-200 nM Incubation Time: 3 days Result: Showed growth inhibition. Cell Cycle AnalysisCell Line: U87MG cells Concentration: 0-12.5 nM Incubation Time: 48 hours Result: Arrested cells at G0/G1. Western Blot AnalysisCell Line: U87MG cells Concentration: 0.39-12.5 nM Incubation Time: 3 hours Result: Selectively inhibited p-RPS6 S235/236 and p-4EBP1 T37/46 at doses as low as 1.56 nM. The mTORC2 targets p-AKT S473 , p-SGK1 S78 , and p-NDRG1 T346 , and the p-AKT S473 target p-GSK3β S9 was inhibited only at high doses. In Vivo RapaLink-1 (i.p.; every 5 days for 25 days, then once a week for 11 week) shows potent anti-tumor efficacy . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: BALB/ Cnu/nu mice bearing U87MG intracranial xenografts 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. Form:Solid IC50& Target:mTOR

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