Rapalink-1

第三代二价 mTOR 抑制剂 RapaLink-1 通过惰性化学接头将雷帕霉素与 MLN0128 结合。 RapaLink-1 显示出比雷帕霉素或 mTOR 激酶抑制剂 (TORKi) 更好的功效，可有效阻断癌症衍生的激活 mTOR 突变体。 RapaLink-1 可以穿过血脑屏障。 RapaLink-1 与 FKBP12 的结合导致 mTORC1 的靶向和持久抑制。 RapaLink-1 通过改善自噬在抗磷脂综合征中发挥抗血栓作用。抗癌活性。

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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.

参考文献:
[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.