Mighty RapaLink-1 vanquishes undruggable mutant mTOR in glioblastoma

Recent emergence of a third generation of mechanistic target of rapamycin (mTOR) inhibitors, termed RapaLink-1, have generated hope in treatment of glioblastoma, the most aggressive primary brain tumor in adults. Produced by coupling first and second generation mTOR inhibitors (1), RapaLink-1 displays superior efficacy in inhibition of the mTOR complex I (mTORC1) pathway. This led to the inhibition of proliferation with relatively longer durability in glioblastoma cells and xenograft models. Importantly, RapaLink-1 crosses the blood-brain barrier and effectively targets mutant mTOR glioblastoma cells. RapaLink-1 is a bivalent inhibitor generated by combining the analogue inhibitor of mTOR, rapamycin, with the ATP-competitive inhibitor of mTOR, MLN0128. The resulting compound is more potent than first- and second-generation mTOR inhibitors. Investigation by Fan et al. [2017] (1) examined the effect of RapaLink-1 and RapaLink-2 on glioblastoma cell growth and proliferation by targeting the mTORC1.