Rapalink-1

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Background

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).
The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Two generation of mTOR inhibitor had been developed.
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 accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR.

[1] Fan Q1, Aksoy O1, Wong RA1, et al., 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.
[2] Rodrik-Outmezguine VS1, Okaniwa M2, Yao Z1, et al., 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.