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

Rapalink-1 is more potent than first- and second-generation mTOR inhibitors. RapaLink-1 could more potently reduce levels of both p-4EBP1 and cell proliferation. Researches compared rapamycin, RapaLink-1, and MLN0128 in LN229 and U87MG. Both growth inhibition and arrest in G0/G1 were more potent in response to RapaLink-1, compared with rapamycin or MLN0128. RapaLink-1 shows potent anti-tumor efficacy in vivo. RapaLink-1 led to initial regression and subsequent stabilization of tumor size in a xenograft model, while tumors treated with vehicle, rapamycin, or MLN0128 grew steadily.

RapaLink-1 could durably block mTORC1. RapaLink-1 is associated with FKBP12, an abundant mTOR-interacting protein, enabling the accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR.