Small molecules bind human mTOR protein and inhibit mTORC1 specifically

Allen, Sonia; Tomilov, Alexey; Cortopassi, Gino A

doi:10.1016/j.bcp.2018.07.013

Cited by 13 publications

(11 citation statements)

References 26 publications

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“… 159 , 160 Beta-blockade is accompanied by up-regulation of AMPK, 161 , 162 and carvedilol up-regulates PGC-1α 163 and appears to enhance autophagic flux through SIRT1 stimulation 164 and by mTOR inhibition. 165 Spironolactone activates SIRT1/AMPK in the heart, 166 and its action to inhibit Akt/mTOR signalling has been linked to its effect to promote autophagic flux. 167 , 168 PGC-1α activation can interfere with the deleterious actions of mineralocorticoid receptor activation.…”

Section: Importance Of Longevity Gene Signalling and Autophagy Modulamentioning

confidence: 99%

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Packer

2020

European Heart Journal

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The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

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Section: Importance Of Longevity Gene Signalling and Autophagy Modulamentioning

confidence: 99%

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Packer

2020

European Heart Journal

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“…Previously our lab has shown that members of the piperazine drug class are mTORC1 specific inhibitors (18). In Figure 1, we show that three piperazines dose dependently inhibit the downstream target of mTORC1, pS6K (Figure 1).…”

Section: Piperazine Compounds Dose Dependently Inhibit Mtorc1 Downstrmentioning

confidence: 62%

“…We recently demonstrated that a series of piperazine compounds are also mTORC1 inhibitors (18). mTORC1 activity is a validated clinical target, and the mTORC1 inhibitor rapamycin, everolimus, and temsirolimus, have been used in clinical trials of GBM (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Novel mTORC1 inhibitors kill Glioblastoma stem cells

Sandoval

Tomilov

Datta

et al. 2020

Preprint

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Glioblastoma Multiforme (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. mTORC1 regulates cell proliferation and has been shown by others to have reduced activity in GBMSC.We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed piperazine-mTOR binding strength by two biophysical measurements--biolayer interferometry and field effect biosensing, and these confirmed each other and demonstrated a structure-activity relationship. Since mTORC1 is reduced in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy--but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, the tight-binding Meclizine provoked 'synthetic lethality' in IDH1-mutant GBMSCs. These data tend to support a novel clinical strategy for GBM, i.e. the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM, and IDH1-mutant GBM.

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“…Cinnarizine also affected the function of radiation and could be used as a radiosensitizer for murine tumors [ 47 , 48 ]. Allen et al found that cinnarizine inhibited mammalian target of rapamycin (mTOR) protein and mTOR complex 1 for anti-tumor therapy [ 49 ]. Deka et al screened and identified cinnarizine as an anti-cancer drug for breast cancer using an integrating virtual screening biochemical experimental approach [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of signal recognition particle 14 as a prognostic biomarker predicting overall survival in patients with acute myeloid leukemia

2021

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Background This study aimed to determine and verify the prognostic value and potential functional mechanism of signal recognition particle 14 (SRP14) in acute myeloid leukemia (AML) using a genome-wide expression profile dataset. Methods We obtained an AML genome-wide expression profile dataset and clinical prognostic data from The Cancer Genome Atlas (TCGA) and GSE12417 databases, and explored the prognostic value and functional mechanism of SRP14 in AML using survival analysis and various online tools. Results Survival analysis showed that AML patients with high SRP14 expression had poorer overall survival than patients with low SRP14 expression. Time-dependent receiver operating characteristic curves indicated that SRP14 had good accuracy for predicting the prognosis in patients with AML. Genome-wide co-expression analysis suggested that SRP14 may play a role in AML by participating in the regulation of biological processes and signaling pathways, such as cell cycle, cell adhesion, mitogen-activated protein kinase, tumor necrosis factor, T cell receptor, DNA damage response, and nuclear factor-kappa B (NF-κB) signaling. Gene set enrichment analysis indicated that SRP14 was significantly enriched in biological processes and signaling pathways including regulation of hematopoietic progenitor cell differentiation and stem cell differentiation, intrinsic apoptotic signaling pathway by p53 class mediator, interleukin-1, T cell mediated cytotoxicity, and NF-κB-inducing kinase/NF-κB signaling. Using the TCGA AML dataset, we also identified four drugs (phenazone, benzydamine, cinnarizine, antazoline) that may serve as SRP14-targeted drugs in AML. Conclusion The current results revealed that high SRP14 expression was significantly related to a poor prognosis and may serve as a prognostic biomarker in patients with AML.

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Small molecules bind human mTOR protein and inhibit mTORC1 specifically

Cited by 13 publications

References 26 publications

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Novel mTORC1 inhibitors kill Glioblastoma stem cells

Identification and validation of signal recognition particle 14 as a prognostic biomarker predicting overall survival in patients with acute myeloid leukemia

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