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| Status |
Public on Apr 05, 2021 |
| Title |
Selective Inhibitors of mTORC1 Activate 4EBP1 and Suppress Tumor Growth |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| 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)
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| Contributor(s) |
Liu H, Lorent J, Larsson O |
| Citation(s) |
34168367 |
| Submission date |
Oct 03, 2019 |
| Last update date |
Mar 18, 2022 |
| Contact name |
Ola Larsson |
| E-mail(s) |
ola.larsson@ki.se
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| Phone |
+46 (0)8 517 73280
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| Organization name |
Karolinska Institutet
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| Department |
Department of oncology-pathology
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| Street address |
CCK, R8:01
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| City |
Stockholm |
| ZIP/Postal code |
171 76 |
| Country |
Sweden |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (50)
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| Relations |
| BioProject |
PRJNA575792 |
| SRA |
SRP224308 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE138417_RAW.tar |
251.6 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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