GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
Series GSE138417 Query DataSets for GSE138417
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
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.
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)
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
Phone +46 (0)8 517 73280
Organization name Karolinska Institutet
Department Department of oncology-pathology
Street address CCK, R8:01
City Stockholm
ZIP/Postal code 171 76
Country Sweden
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (50)
GSM4107721 cyto_RMC4627_1A
GSM4107722 poly_RMC4627_1A
GSM4107723 cyto_RMC4745_1A
BioProject PRJNA575792
SRA SRP224308

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE138417_RAW.tar 251.6 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap