Rapalink-1

RapaLink-1 (CAS: 1887095-82-0) is a third-generation mTOR inhibitor. It uniquely combines the binding pockets of first- and second-generation mTOR kinase inhibitors, creating a bivalent interaction that enables it to inhibit mutations that are resistant to previous TORKi (mTOR kinase inhibitors).

The PIK3CA–AKT–mTOR signaling pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small molecule inhibitors targeting multiple nodes of this pathway. Two generations of mTOR inhibitors have already been developed.

Compared to first- and second-generation mTOR inhibitors, RapaLink-1 is more potent. RapaLink-1 can more effectively reduce the levels of p-4EBP1 and inhibit cell proliferation. Researchers compared the efficacy of rapamycin, RapaLink-1, and MLN0128 in LN229 and U87MG cells. Compared to rapamycin or MLN0128, RapaLink-1 exhibited stronger growth inhibition and a greater ability to arrest cells in the G0/G1 phase. In vivo, RapaLink-1 demonstrated potent antitumor activity; in xenograft tumor models, it led to tumor regression and subsequent stabilization of tumor volume, whereas tumors in the vehicle, rapamycin, or MLN0128 groups continued to grow steadily.

RapaLink-1 can durably block mTORC1. RapaLink-1 is associated with FKBP12, an abundant mTOR-interacting protein, which allows RapaLink-1 to aggregate. Compared to rapamycin or other TORKi, RapaLink-1 shows better efficacy and can potently inhibit cancer-derived, mTOR-activating mutations.