Torin1 / InvivoGen - LARVOL DELTA

Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling. (PubMed, Cell Rep) - "Here, we show that the nutrient sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) is rapidly activated by glucose in β cells via the insulin secretion machinery, positioning mTORC1 as a sensor of β cell activity...Mechanistically, mTORC1 promotes RhoA activation and F-actin polymerization, limiting vesicle movement and dampening the second phase of insulin secretion. These findings identify a glucose-mTORC1-RhoA signaling axis that forms an autonomous feedback loop to constrain insulin exocytosis, providing insight into how β cells prevent excessive insulin release and maintain metabolic balance."

Journal • RHOA

mTOR Signalling in Arbovirus Infections: Molecular Mechanisms and Therapeutic Opportunities. (PubMed, Rev Med Virol) - "Rapamycin and its derivatives reduce viral replication and improve survival in preclinical models, while repurposed drugs like niclosamide and chloroquine exhibit antiviral effects against ZIKV. ATP-competitive inhibitors such as Torin-1 and natural compounds like resveratrol expand the therapeutic landscape. Combination therapies pairing mTOR inhibitors with antivirals or immune modulators may provide synergistic benefits. This review highlights the molecular mechanisms underlying arbovirus manipulation of mTOR signalling and emphasises the potential of tailored therapeutic interventions targeting these pathways to mitigate arbovirus-associated diseases."

Journal • Review • CNS Disorders • Dengue Fever • Infectious Disease

Inactivation of mTOR is a strategy for tumor resistance to ribosome biogenesis inhibition (AACR 2025) - "The findings were validated using chemical inhibition of mTOR by Torin-1, a catalytic mTOR inhibitor and genetic knockout of an activator of mTOR signaling...In summary, we uncover a new non-genetic model of cancer drug resistance termed as translational fitness that enables cells to survive severe translational repression. These findings reveal an unexpected complication by mTOR inhibitory strategies and have implications for exploring effective drug combinations in cancer therapy."

Colorectal Cancer • Oncology • Solid Tumor

MLST8 overexpression in RPE cells disrupts autophagy through novel mechanisms affecting AMD pathogenesis. (PubMed, Autophagy) - "Using our uniquely developed MLST8 (MTOR associated protein, LST8 homolog) knock-in animal model with RPE-specific overexpression, which drives MTOR (mechanistic target of rapamycin kinase) upregulation, we demonstrate that increased MTOR complexes 1 and 2 in the RPE disrupts macroautophagy/autophagy by suppressing autophagosome formation genes and impairing MAP1LC3/LC3 processing. Notably, MTOR inhibition with torin1 treatment or CRYBA1 overexpression rescues these defects, restoring autophagy and RPE integrity. Our findings reveal that autophagy disruption mediated by both MTORC1 and MTORC2 drives AMD-like pathology in our mouse model, establishing autophagy regulation as a promising avenue for therapeutic intervention in this vision-threatening disease."

Journal • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders

Constitutive hepatic mTORC1 activation aggravates alcohol-induced liver injury via endoplasmic reticulum stress-mediated ferroptosis. (PubMed, Am J Pathol) - "Torin-1, an ATP-competitive mTOR inhibitor, suppressed the mTORC1 activity and reversed the effects of Depdc5 deletion on ER stress and ferroptosis in ethanol-fed mouse livers. Furthermore, pharmacological relief of ER stress using TUDCA or inhibition of ferroptosis with liproxstatin-1 both alleviated the liver abnormalities induced by Depdc5 ablation in ethanol-fed mice. Additionally, the research uncovered that ER stress functions as an upstream signal of ferroptosis in the progression of ALD. These findings provide novel in vivo evidence that sustained mTORC1 activation leads to alcoholic liver injury by inducing ER stress and ferroptosis, suggesting that targeting these pathways may represent a potential therapeutic strategy for ALD."

Journal • Fibrosis • Hepatology • Immunology • Liver Failure • DEPDC5

Activation of autophagy mediated by PI3K/Akt/mTOR signalling cascade alleviates impaired adipose-derived stem cell osteogenesis in a diabetic microenvironment. (PubMed, Br J Pharmacol) - "AGEs decreased the osteogenesis of ASCs by activating PI3K/Akt/mTOR signalling cascade and blocking autophagic flux. Autophagy induced by blocking the PI3K/Akt/mTOR signalling cascade could rescue the negative influences of ASCs in diabetic environment and provide a potential therapeutic strategy for bone renewal in individuals with DOP."

Journal • Osteoporosis • Rheumatology • RUNX2

Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine Resistant Multiple Myeloma. (PubMed, Mol Cancer Res) - "Indeed, mTOR inhibition with Torin 1 restored partial sensitivity to omacetaxine in both resistant cell lines. These results provide a rational approach for omacetaxine-based combination in patients with multiple myeloma, which have historically shown better responses to multi-agent regimens. Implications: Through the use of ribosome profiling, our findings indicate mTOR inhibition as a novel combination therapy for partnering with the translation inhibitor omacetaxine in the treatment of multiple myeloma."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Autophagy regulates cellular senescence by mediating the degradation of CDKN1A/p21 and CDKN2A/p16 through SQSTM1/p62-mediated selective autophagy in myxomatous mitral valve degeneration. (PubMed, Autophagy) - "MTOR-dependent autophagy induced by rapamycin and torin-1 attenuated cell senescence and decreased the expression of cyclin-dependent kinase inhibitors (CDKIs) CDKN2A/p16INK4A and CDKN1A/p21CIP1...Notably, CDKN1A and CDKN2A localized to autophagosomes and lysosomes following MTOR antagonism or MG132 treatment...Our findings are the first demonstration that CDKN1A and CDKN2A are degraded through SQSTM1-mediated selective autophagy, independent of the ubiquitin-proteasome pathway. These data will inform development of therapeutic strategies for the treatment of canine and human MMVD, and for the treatment of Alzheimer disease, Parkinson disease and other age-related degenerative disorders."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Movement Disorders • Parkinson's Disease • Targeted Protein Degradation • CDKN1A • CDKN2A • SQSTM1 • TGFB1

Activated mTOR Signaling in the RPE Drives EMT, Autophagy, and Metabolic Disruption, Resulting in AMD-Like Pathology in Mice. (PubMed, Aging Cell) - "The mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are crucial for various physiological functions. Aging in these mice leads to RPE degeneration, causing retinal damage, impaired debris clearance, and metabolic and mitochondrial dysfunction. Inhibition of mTOR with TORIN1 in vitro or βA3/A1-crystallin in vivo normalized mTORC1/2 activity and restored function, revealing a novel role for the mTOR complexes in regulating RPE function, impacting retinal health and disease."

Journal • Preclinical • Age-related Macular Degeneration • Macular Degeneration • Metabolic Disorders • Ophthalmology • Retinal Disorders

An mTOR inhibitor discovery system using drug-sensitized yeast. (PubMed, Geroscience) - "Inhibition of the target of rapamycin (TOR/mTOR) protein kinase by the drug rapamycin extends lifespan and health span across diverse species...In contrast, 100 nM Torin1 and 500 nM GSK2126458 (omipalisib) are sufficient to identify TOR1-dependent growth inhibition in the drug-sensitized background...Additionally, for the TOR inhibitor AZD8055, the drug-sensitive system resolves that the compound results in TOR1-dependent growth sensitivity at 100 µM, whereas no growth inhibition is observed in a wild-type yeast strain background. Our platform also identifies the caffeine analog aminophylline as a TOR1-dependent growth inhibitor via selective tor1 growth sensitivity. We also tested nebivolol, isoliquiritigenin, canagliflozin, withaferin A, ganoderic acid A, and taurine and found no evidence for TOR inhibition using our yeast growth-based model. Our results demonstrate that this system is highly effective at identifying compounds that inhibit the TOR..."

Journal • Oncology

Synthesis and structural modification of the natural product Ivesinol to discover novel autophagy activators. (PubMed, Eur J Med Chem) - "Specifically, the derivative B2 significantly activated autophagy activity in concentration- and time-dependent manners, and even outperformed the commonly used activator Torin1 in activating autophagy in MCF-7 cells at 0.5 μM...Based on these findings, we proposed that B2 activates autophagy by mechanisms involved in downregulation of key HSP70 family members, activation of the UPR, and ultimately leading to autophagy. In conclusion, we suggest that B2 could be a promising and valuable autophagy activator with significant potential for further development."

Journal • Targeted Protein Degradation

Rapamycin Abrogates Aggregation of Human α-Synuclein Expressed in Fission Yeast via an Autophagy-Independent Mechanism. (PubMed, Genes Cells) - "Notably, rapamycin, a natural product that allosterically inhibits the mammalian target of rapamycin (mTOR) by forming a complex with FKBP12, and Torin1, a synthetic mTOR inhibitor that blocks ATP binding to mTOR, markedly reduced the number of cells harboring α-Syn aggregates...Importantly, the effect of rapamycin was also observed in the cells lacking atg1+, a key regulator of autophagy. Collectively, rapamycin abrogates human α-Syn aggregation expressed in fission yeast via an autophagy-independent mechanism mediated by FKBP12."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

nprl2 KO Results in mtorc1-dependent Abnormalities in Neuronal Morphology, Migration, and Network Function in a Mouse Model of Focal Cortical Dysplasia (AES 2024) - "Dams were injected with rapamycin, torin1, rapalink, or an mTORC2 inhibitor 24 hrs after surgery. Nprl2 KO via in utero electroporation recapitulates the phenotypes observed in resected brain specimens harboring mTOR pathway variants including mTOR pathway hyperactivation, increased soma diameter, and heterotopic white matter neurons. While KO animals did not have spontaneous seizures, mTOR-dependent changes in seizure threshold were observed. Interestingly, histological and electrographic abnormalities were corrected by mTORC1 but not mTORC2 inhibition indicating that disease phenotypes in GATOR1 subunits are highly mTORC1-dependent."

Preclinical • CNS Disorders • Epilepsy • BCL11B • CUX1 • DEPDC5

Knockout of Mtor Pathway Regulators Results in mtorc1-dependent Cellular Aggregation (AES 2024) - "Treatment groups were rapamycin (50 nM; 48hrs), torin1 (50 nM; 48 hrs), or an mTORC2 inhibitor (50 nM; 48 hrs). Abnormal cellular aggregation is an mTORC1-dependent phenotype that occurs in vitro, following KO of DEPDC5, TSC2, STRADa, and KPTN. This phenotype is also not dependent of mTORC2 activation. These observations point toward enhanced cellular aggregation as common phenotype across mTORopathies, and may play a role in several hallmark phenotypes observed in brain specimens harboring these variants."

CNS Disorders • Epilepsy • DEPDC5 • TSC2

Accelerated growth of preadipocyte cultures with TSC1 downregulation might be linked to lipoma development and can be reversed by mTOR or PI3K inhibition (ESPE 2024) - "TSC1 knockdown cells were treated with inhibitors of mTOR (rapamycin and torin-1) and Phosphoinositide-3- (PI3)-kinase (alpelisib). Since downregulation of TSC1 led to increased proliferation of SGBS preadipocytes, a causative relationship of the loss-of-function TSC1 variant to lipoma formation is likely in our patient. A tumor regression could not be observed during a 6-month treatment attempt with the rapalog sirolimus. Other rapalogs or PI3-kinase inhibition might be alternative treatment options for the lipoma."

Late-breaking abstract • Brain Cancer • Developmental Disorders • Oncology • TSC1

mTOR Inhibitors Modulate the Biological Nature of TGF-β2-Treated or -Untreated Human Trabecular Meshwork Cells in Different Manners. (PubMed, Biomedicines) - "To study the effects of the mTOR inhibitors rapamycin (Rapa) and Torin1 on the glaucomatous HTM, transforming growth factor-β2 (TGF-β2)-treated two-dimensionally (2D) and three-dimensionally (3D) cultured HTM cells were used...The diverse effects of mTOR inhibitors on TGF-β2-untreated and TGF-β2-treated spheroids were also observed in the mRNA expression of extracellular matrix proteins. The results taken together suggest that mTOR inhibitors significantly influence the biological aspects of both a single layer and multiple layers of the TGF-β2-treated HTM and untreated HTM."

Journal • Glaucoma • Ophthalmology • MAP1LC3B • TGFB1

FUS activity at synapses is modulated through mechanistic target of rapamycin complex 2 (mTORC2) (ALS-MND 2024) - "In primary mouse neuron cultures, we used pharmacological modulators of the mTOR pathway: torin1, which inhibits both mTORC1 and mTORC2, and rapamycin, which inhibits only mTORC1. Both torin1 or rapamycin treatments caused an increase in FUS localization to the cytoplasm and dendrites of primary neurons. However, ex-vivo experiments using acute mouse brain slices treated show that only torin1 promotes an increase in FUS in synaptoneurosomes (SNs), suggesting that FUS activity at synapses is modulated in an mTORC2-dependent manner."

Oncology • Sarcoma • Solid Tumor • FUS

mTORC1 activity licenses its own release from the lysosomal surface. (PubMed, Mol Cell) - "Mechanistically, "inactive" mTORC1 causes persistent Rag activation, underlining its release as another process actively mediated via the Rags. In sum, we describe a mechanism by which mTORC1 controls its own localization, likely to prevent futile cycling on and off lysosomes."

Journal • TFEB

Identification of Key Immune and Cell Cycle Modules and Prognostic Genes for Glioma Patients through Transcriptome Analysis. (PubMed, Pharmaceuticals (Basel)) - "In conclusion, our study provides valuable insights into molecular mechanisms and identifying potential therapeutic targets for gliomas."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor

Identification and a mode of action of bisabosqual A, a novel asparagine synthetase (ASNS) inhibitor, towards the development of molecular-targeted anticancer drug (EORTC-NCI-AACR 2024) - "Moreover, Bis A induced negative feedback pathways containing the GCN2-eIF2α-ATF4, PI3K-AKT-mTORC1 and RAF-MEK-ERK axes, but combination treatment of Bis A and rapamycin/torin-1 overcame the potential drug resistance triggered by mTOR pathways. Bis A could be a promising lead molecule to further develop potent ASNS inhibitors. Besides, our data revealed that the combination treatment of Bis A with L-ASNase or the mTORC1 inhibitor is a potential strategy for cancer chemotherapy."

Acute Lymphocytic Leukemia • Breast Cancer • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • ASNS • ATF4

Early divergent modulation of NLRP2's and NLRP3's inflammasome sensors vs. AIM2's one by signals from Aβ•Calcium-sensing receptor complexes in human astrocytes. (PubMed, Brain Res) - "These effects were specific, being significantly hindered by NPS2143 and inhibitors of PI3K (LY294002), AMPKα (Dorsomorphin), mTOR (Torin1), and JAK/TYK (Brepoticinib). The neatly divergent modulation of NLRP3's vs. AIM2's PRR proteins by Aβ•CaSR cues and by Bay11-7082 suggests that, when bacterial or viral DNA fragments are absent, AIM2 might play "anti-inflammasomal" or other roles in HCAs. However, Bay11-7082's no effect on NLRP2 PRR overexpression also reveals that CaSR's downstream mechanisms controlling inflammasomes' sensors are quite complex in HCAs, and hence, given AD's impact on human health, well worth further studies."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Melanoma • Oncology • Solid Tumor • AIM2 • Aβ42 • IL18 • IL1B • IL6 • NLRP2 • NLRP3

RBP4 REGULATES APAP-INDUCED LIVER INJURY BY TARGETING MITOCHONDRIA (AASLD 2024) - "Notably, CCK8 assays revealed that neither autophagy inhibitors (rapamycin) nor enhancers (Torin1) improved cell viability under AR treatment. Elevated RBP4 levels during APAP overdose exacerbate hepatocyte mitochondrial damage and liver injury. This process can be ameliorated by transiently enhancing mitochondrial autophagy."

Hematological Disorders • Hepatology • Liver Failure • RBP4

Apache is a neuronal player in autophagy required for retrograde axonal transport of autophagosomes. (PubMed, Cell Mol Life Sci) - "APache silencing causes a blockade of autophagic flux preventing the clearance of p62/SQSTM1, leading to a severe accumulation of autophagosomes and amphisomes at synaptic terminals and along neurites due to defective retrograde transport of TrkB-containing signaling amphisomes along the axons. Together, our data identify APache as a regulator of the autophagic cycle, potentially in cooperation with AP-2, and hypothesize that its dysfunctions contribute to the early synaptic impairments in neurodegenerative conditions associated with impaired autophagy."

Journal • CNS Disorders • SQSTM1 • TFAP2A

Integrating mTOR Inhibition and Photodynamic Therapy Based on Carrier-Free Nanodrugs for Breast Cancer Immunotherapy. (PubMed, Adv Healthc Mater) - "In this study, a carrier-free nanodrug formulation composed of Torin 1 as mTORC1/C2 dual inhibitor and Verteporfin as a photosensitizer and Yes-associated protein inhibitor is developed. In this way, the nanodrugs can reverse PDT-elicited angiogenesis and promote cancer immunotherapy to eliminate tumor tissues and prevent metastasis. This nanosystem provides insights into integrating mTOR inhibitors and photosensitizers for safe and effective breast cancer treatment in clinical settings."

Journal • Breast Cancer • Fibrosis • Immunology • Oncology • Solid Tumor

The mTOR pathway controls phosphorylation of BRAF at T401. (PubMed, Cell Commun Signal) - "Importantly, the BRAF/RAF1 inhibitor naporafenib, the MEK inhibitor trametinib and the ERK inhibitor ulixertinib failed to reduce pT401 levels in these settings, supporting an alternative ERK-independent pathway to T401 phosphorylation...Conversely, genetic mTOR pathway activation by oncogenic RHEB (Q64L) and mTOR (S2215Y and R2505P) mutants substantially increased pT401, an effect that was reverted by dactolisib and torin1 but not by trametinib...Using mass spectrometry, we provide further evidence that torin1 suppresses the phosphorylation of T401, S405 and S409 but not of other important regulatory phosphorylation sites such as S446, S729 and S750. In summary, our data identify the mTOR axis and its inhibitors of (pre)clinical relevance as novel modulators of BRAF phosphorylation at T401."

Journal • Oncology • BRAF • RHEB