Project name: Selective Inhibitors of mTORC1 Activate 4EBP1 and Suppress Tumor Growth

Description: The clinical benefit of current mTOR inhibitors is limited, perhaps reflecting their intrinsic pharmacological profiles. Rapamycin analogs selectively inhibit mTORC1, but fail to suppress phosphorylation of the mTORC1 substrate 4EBP1, a translational repressor that is a key driver of oncogenic mTORC1 signaling. mTOR kinase active-site inhibitors fully suppress mTORC1 and phosphorylation of its substrates, but are active against mTORC2 and additional kinases, potentially contributing to tolerability limitations. The prototype bi-steric inhibitor RapaLink-1 exploits the selective mTORC1 interactions of rapamycin and the broad mTOR kinase inhibitory effects of an active-site inhibitor, through covalent linkage of the two pharmacophores to achieve complete mTORC1/2 inhibition. We demonstrate that the anti-proliferative activity of RapaLink-1 is dependent upon mTORC1 and suppression of 4EBP1 phosphorylation. Using a rational design strategy, we tuned the affinities of the rapamycin core and ATP-mimetic moieties to create novel bi-steric inhibitors with enhanced mTORC1 selectivity and potency against 4EBP1 phosphorylation. mTORC1-selective bi-steric compounds produced durable inhibition of 4EBP1 phosphorylation in vitro and in vivo, and drove tumor regressions at well-tolerated doses in xenograft models of breast cancer.Overall design: 4 biological replicates of MCF7 cells under one of the following conditions: Starvation, Full serum + DMSO, Full serum + MLN0128, Full serum + RMC-4627, Full serum + RMC-4745. RMC-4627 and RMC-4745 are selective inhibitors of mTORC1 developed within this study. For one of the biological replicate (replicate 1), we provided 2 technical replicates (1A and 1B)

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: Medical

Last updated: 2019-10-03