torkinib (PP242) / Takeda, UCSF Medical Center - LARVOL DELTA

Molecular markers in brain metastases: Role of PI3K/mTOR pathway in epithelial-to-mesenchymal transition [WITHDRAWN] (AACR 2025) - "Epithelial (E-cadherin) and mesenchymal (Vimentin) expression were analyzed following inhibition of the mTOR pathway using mTOR complex 1 (mTORC1) inhibitor (rapamycin), combined mTORC1/2 inhibitor (PP242), or with SiRNAs targeting mTOR, Raptor and Rictor. These results provide evidence that the mTOR pathway is involved in metastatic brain tumors, suggesting its critical role in achieving a metastatic potential to the brain. Furthermore, these findings point to its role in diagnosis, prognosis, and clinical management in patients with metastatic brain tumors."

Biomarker • Brain Cancer • Breast Cancer • Oncology • Solid Tumor • AKT1 • CD44 • CDH1 • STAT3 • VIM

Induction of Triple Negative Breast Cancer Cell Death and Chemosensitivity using mTORC2-directed RNAi Nanomedicine. (PubMed, Cancer Res Commun) - "The mTOR kinase inhibitor PP242 blocks both mTORC1 and mTORC2, which decreases growth and survival of RICTOR-amplified TNBC cells...Rictor silencing blocked tumor mTORC2 signaling and growth in multiple TNBC mouse models while also improving TNBC tumor response to chemotherapy. These findings support the further development of technologies for therapeutic Rictor silencing as an effective approach for mTORC2-selective inhibition and treatment in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • RICTOR

Identification of a Novel Stomatal Opening Chemical, PP242, That Inhibits Early Abscisic Acid Signal Transduction in Guard Cells. (PubMed, Plant Cell Physiol) - "Previously, we identified a target of rapamycin (TOR) inhibitor, temsirolimus, to induce stomatal opening through chemical screening. However, PP242 still induced stomatal opening in this mutant, suggesting that PP242 also targets other guard cell components. Together, these results reveal that PP242 induces stomatal opening partly by inhibiting steady-state ABA signal transduction."

Journal

Cytochrome P450 Is a Metabolic Regulator of Diabetic Kidney Disease (DKD) Progression (KIDNEY WEEK 2024) - "To study the preclinical significance, molecular and histological analyses were performed using a T2DM mouse model treated with the pharmacological inhibitors of 20-HETE (HET0016), sEH (AUDA), SGLT2 (Dapagliflozin), and mTOR (Rapamycin, JR-AB2-011 and PP242). This study provides a framework into novel CYP450 pathways involved in diabetes-induced renal injury.We also describe the potential prognostic and diagnostic biomarkers related to CYP associated pathways in the progression DKD"

Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • CYP2B6 • NOX4

Casein kinase 1α mediates phosphorylation of the Merkel cell polyomavirus large T antigen for β-TrCP destruction complex interaction and subsequent degradation. (PubMed, mBio) - "Inhibition of CK1α using short hairpin RNA (shRNA) and treatment of a CK1α inhibitor or an mTOR inhibitor, TORKinib, resulted in decreased β-TrCP interaction with LT, increased LT expression, and enhanced MCPyV replication...Therefore, cellular kinase pathways are indispensable for governing MCPyV polyomavirus infection and life cycle in coordinating with the immunosuppression environment at disease onset. Understanding the regulation mechanisms of MCPyV replication by viral and cellular factors will guide proper prevention strategies with targeted inhibitors for MCPyV-associated Merkel cell carcinoma (MCC) patients, who currently lack therapies."

Journal • Infectious Disease • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • Targeted Protein Degradation • CSNK1A1 • CUL1

LUHMES Cells: In Vitro Model for Studying Tauopathy in Alzheimer's Disease (AAIC 2024) - "One study revealed that PP242, a dual inhibitor of mTORC1 and mTORC2, could reverse fenazaquin-induced tau aggregation in LUHMES cells...These cells have endogenous tau expression, a key characteristic differentiating this line from more commonly used cell lines, such as HEK293 and SH-SY5Y. Significant progress toward evaluating effective treatments can be made by using the LUHMES cell line to study AD-related tauopathy pathology."

Preclinical • Alzheimer's Disease • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

TFEB/LAMP2 contributes to PM0.2-induced autophagy-lysosome dysfunction and alpha-synuclein dysregulation in astrocytes. (PubMed, J Environ Sci (China)) - "Moreover, with the transcription factor EB (TFEB) subcellular localization and the increase in LC3II, LAMP2, CTSB, and cathepsin D proteins were identified, leading to the restoration of the degradation of α-syn after the intervention of PP242. Our results identified that PM0.2 exposure could promote the α-syn pathological dysregulation in astrocytes, providing mechanistic insights into how PM0.2 increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM0.2 toxicity."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • CTSB • CTSD • LAMP2 • TFEB

A Potential Combination of Targeting HSP90 and mTOR in Breast Cancer Cell Growth, Migration, and Invasion Through Inhibiting AKT Phosphorylation and F-actin Organization. (PubMed, Anticancer Res) - "Targeting HSP90 and mTOR has the potential to suppress breast cancer cell growth and progression by disrupting AKT signaling and inhibiting F-actin polymerization. This combination treatment may hold promise as a therapeutic strategy for breast cancer treatment that ameliorates adverse effects of a single treatment."

Journal • Breast Cancer • Oncology • Solid Tumor • CDC37 • HSP90AA1

Inhibition of mTORC2 promotes natriuresis in Dahl salt-sensitive rats via the decrease of NCC and ENaC activity. (PubMed, Am J Physiol Renal Physiol) - "Acute effects of PP242 on natriuretic, diuretic, and kaliuretic responses were determined in unanesthetized SS rats utilizing benzamil, furosemide, or hydrochlorothiazide (inhibitors of ENaC, NKCC2, or NCC, respectively) either administered alone or in combination. Evidence also indicated that PP242 also prevents the loss of K+ associated with the inhibition of NCC. These findings suggest that PP242 may represent an improved therapeutic approach for antihypertensive intervention, potentially controlling blood pressure and mitigating kidney injury in salt-sensitive human subjects."

Journal • Preclinical • Cardiovascular • Hypertension • Inflammation • Renal Disease

Integrative informatics analysis identifies that ginsenoside Re improves renal fibrosis through regulation of autophagy. (PubMed, J Nat Med) - "In addition, induction of autophagy with PP242 neutralized the anti-fibrotic effects of G-Re...A combination of informatics analysis and biological experiments confirmed that ginsenoside Re could improve renal fibrosis and kidney function through the regulation of autophagy. These findings provide important insights into the mechanisms of G-Re's protective effects in kidney injuries."

Journal • Acute Kidney Injury • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • TGFB1

Long non-coding RNA MLLT4 antisense RNA 1 induces autophagy to inhibit tumorigenesis of cervical cancer through modulating the myosin-9/ATG14 axis. (PubMed, Sci Rep) - "In this research, we show that the long non-coding RNA MLLT4 antisense RNA 1 (lncRNA MLLT4-AS1) is induced by the MTORC inhibitor PP242 and rapamycin in cervical cells. Mechanically, MLLT4-AS1 was associated with the myosin-9 protein, which further promoted the transcription activity of the ATG14 gene. In conclusion, we demonstrated that MLLT4-AS1 acts as a potential tumor suppressor in cervical cancer by inducing autophagy, and H3K27ac modification-induced upregulation of MLLT4-AS1 could cause autophagy by associating with myosin-9 and promoting ATG14 transcription."

Journal • Cervical Cancer • Oncology • Solid Tumor • AFDN • MYH9

Rapamycin mitigates inflammation-mediated disc matrix homeostatic imbalance by inhibiting mTORC1 and inducing autophagy through Akt activation. (PubMed, JOR Spine) - "Specifically, different chemical inhibitors including rapamycin, 3-methyladenine, MK-2206, and PP242 were used to modulate activities of different proteins in the PI3K/Akt/mTOR signaling pathway to assess IL-1β-induced cellular senescence, apoptosis, and matrix homeostasis in rAF cells grown under nutrient-poor culture condition. These findings suggest that rapamycin blunts adverse effects of inflammation on disc cells by inhibiting mTORC1 to induce autophagy through the PI3K/Akt/mTOR pathway that is dependent on Akt and mTORC2 activities. Hence, our findings identify autophagy, rapamycin, and PI3K/Akt/mTOR signaling as potential therapeutic targets for IDD treatment."

Journal • Back Pain • Fibrosis • Inflammation • Lumbar Back Pain • Musculoskeletal Pain • Pain • HMGB1 • IL1B • MMP13 • MMP3 • SQSTM1

Activation of Lysosomal Function Ameliorates Amyloid-β-Induced Tight Junction Disruption in the Retinal Pigment Epithelium. (PubMed, Mol Cells) - "Furthermore, clearance of amyloid-β by Torin and PP242 ameliorated the tight junction disruption of RPE in vivo. Overall, our findings suggest mTOR inhibition as a new therapeutic strategy for the restoration of tight junctions in age-related macular degeneration."

Journal • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • LAMP2

Targeting the LXR/mTOR Signaling Axis: A Novel Therapeutic Strategy for Modulating Autophagy in Diabetic Kidney Disease (KIDNEY WEEK 2023) - "T2D mice were treated with different pharmacological drugs to inhibit specific components of the mTOR complex: rapamycin for mTORC1, JR-AB2-011 for mTORC2, and PP242 for mTORC1/mTORC2...In parallel, control mice were treated with Hydroxychloroquine (HCQ), an autophagy inhibitor, to further investigate the role of autophagy High glucose levels or hyperglycemia can lead to podocyte injury and dysregulation of autophagy... This study presents evidence for a novel role of LXR/mTOR in regulating oxidative stress and autophagy during the onset and progression of diabetic kidney disease (DKD)"

Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • NOX4

Prior Treatment with AICAR Causes the Selective Phosphorylation of mTOR Substrates in C2C12 Cells. (PubMed, Curr Issues Mol Biol) - "The exposure of cells to rapamycin (an mTORC1 inhibitor) and PP242 (an inhibitor of both mTOR complexes) revealed the differential phosphorylation of mTORC2 substrates. Taken together, the data suggest that prior exposure to AICAR causes the selective phosphorylation of mTOR substrates, even after prolonged recovery in a nutrient-replete medium."

Journal • AMPK

Sodium Butyrate Induces Mitophagy and Apoptosis of Bovine Skeletal Muscle Satellite Cells through the Mammalian Target of Rapamycin Signaling Pathway. (PubMed, Int J Mol Sci) - "In contrast, the addition of PP242, an inhibitor of the mTOR signaling pathway also inhibited mRNA and protein expression levels of mTOR, AKT1, FOXO1, and EIF4EBP1 and promoted mitophagy and apoptosis, which were consistent with the effect of NaB treatment. NaB might promote mitophagy and apoptosis in BSCs by inhibiting the mTOR signaling pathway. Our results would expand the knowledge of sodium butyrate on bovine skeletal muscle cell state and mitochondrial function."

Journal • AKT1 • EIF4EBP1

mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance. (PubMed, Oncol Res) - "In addition, we confirmed that combination treatment with the mTORC2 inhibitor PP242 and the PARP inhibitor olaparib synergistically inhibited pancreatic cancer growth in vivo. Thus, this study provides a novel target and strategy for optimizing PARP inhibitor efficiency in pancreatic cancers."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • BRCA1 • BRCA2

Local protein synthesis in axons sustains synapse-specific neurotransmission Cyril Hanus | University of Paris (CAN-ACN 2023) - " Using whole-cell recordings to manipulate pre- and postsynaptic neurons independently in acute cortical slices, we observed reduced excitatory postsynaptic responses (EPSP) and increased paired-pulse ratio (PPR) after presynaptic blockade with mTOR inhibitor PP242 (EPSP: 75% ± 4%, n = 12, p < 0.001; ΔPPR = 0.16 ± 0.05, p < 0.01) or M7 cap analog (EPSP: 47% ± 6%, n = 16, p < 0.001; ΔPPR = 0.13 ± 0.05, p < 0.05), indicating that synaptic release is sustained by mTOR and cap-dependent PS... Axonal translation is a fundamental regulatory principle that locally governs information transfer at central synapses and orchestrates excitation-inhibition balance in the neocortex. Protein synthesis has emerged as a promising candidate target for treating neuropathology such as autism spectrum disorder and Alzheimer disease, yet the focus has historically been postsynaptic. Our results highlight the potential for neuropathology interventions that rely..."

Alzheimer's Disease • Autism Spectrum Disorder • CNS Disorders • Genetic Disorders

Treatment for ovarian clear cell carcinoma with combined inhibition of WEE1 and ATR. (PubMed, J Ovarian Res) - "In a selection of 166 compounds we showed that inhibitors of ATR and WEE1 were cytotoxic against a panel of OCCC cell lines. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC."

Journal • Endometriosis • Gynecology • Oncology • Ovarian Cancer • Solid Tumor • Women's Health • ARID1A

Three generations of mTOR kinase inhibitors in the activation of the apoptosis process in melanoma cells. (PubMed, J Cell Commun Signal) - "The following inhibitors were used: protein kinase inhibitors such as AKT-MK-2206, MEK-AS-703026, mTOR-everolimus and Torkinib, as well as dual PI3K and mTOR inhibitor-BEZ-235 and Omipalisib, and mTOR1/2-OSI-027 inhibitor in single-mode and their combinations with MEK1/2 kinase inhibitor AS-703026. There is a need for research on the search for new therapeutic strategies aimed at particular groups of patients. Effect of three generations of mTOR kinase inhibitors on caspase-3 activity, apoptosis and proliferation in melanoma cell lines."

Journal • Melanoma • Oncology • Solid Tumor • CASP3 • MAP2K1

mTOR regulates stem cells of glioblastoma by altering the self-renewal and proliferation (AACR 2023) - "GBM stem cells were treated with various inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126...Treatment with novel small molecule dual inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective...Additionally, Torin2 was able to eradicate tumor cells. Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • NANOG • NES • PTEN

Discovery of helical sulfonyl-γ-AApeptides targeting LC3 in cancer cells (AACR 2023) - "This effect was augmented by the presence of 2 µM autophagy activator PP242... We designed and synthesized novel helical sulfonyl-γ-AApeptide LC3 binders. With the ability of cellular penetration, they demonstrated inhibition of autophagic flux and preliminary cytotoxicity in cancer cells. Future studies may focus on structural activity relationship and further evaluation of its mechanisms of action in cancer cells."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

The Role of Green Tea Catechin Epigallocatechin Gallate (EGCG) and Mammalian Target of Rapamycin (mTOR) Inhibitor PP242 (Torkinib) in the Treatment of Spinal Cord Injury. (PubMed, Antioxidants (Basel)) - "It has been found that EGCG was as effective as PP242 in suppressing mTOR signaling pathways, as evidenced by a reduction in phosphorylated S6 expression (PP242 (t-test, p < 0.0001) or EGCG (t-test, p = 0.0002)). These results demonstrate that EGCG and PP242 effectively suppress mTOR pathways, resulting in recovery from SCI in rats, and that EGCG acts via suppressing mTOR pathways."

Journal • CNS Disorders • Immunology • Inflammation • Orthopedics • Systemic Inflammatory Response Syndrome

Lysosomal dysfunction in Schwann cells is involved in bortezomib-induced peripheral neurotoxicity. (PubMed, Arch Toxicol) - "Remarkably, lysosomal activators PP242 and Torin1, significantly reversed the blockage of autophagic flux by BTZ. Taken together, we identified that lysosomal dysfunction in Schwann cells caused by BTZ is involved in the BIPN pathology. Improved lysosomal function in Schwann cells can be a promising strategy for BIPN treatment."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Pain • CTSB

Defining the role of mTOR pathway in the regulation of stem cells of glioblastoma. (PubMed, Adv Biol Regul) - "Here we explored the role of the mTOR pathway in the regulation of stem cells of GBM by treating them with inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126...Treatment with novel small molecule inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective...Torin2 was able to eradicate tumor cells. In conclusion, Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • NANOG • NES • PTEN