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

Esterase-Responsive Self-Assembled Torkinib Prodrug Nanoparticles Alleviate Atherosclerosis via Macrophage mTOR Inhibition. (PubMed, ACS Appl Mater Interfaces) - "In an ApoE-/- mouse model, LPNP administration significantly reduced plaque burden, increased collagen deposition, and enhanced plaque stability without altering systemic lipid profiles or causing overt toxicity. Collectively, this esterase-responsive prodrug strategy couples carrier-free self-assembly with macrophage-associated intracellular activation, providing a promising approach to enhance lesional macrophage mTOR inhibition for atherosclerosis treatment."

Journal • Atherosclerosis • Cardiovascular • Inflammation • ABCA1 • ABCG1 • APOE

Mechanistic study on TFEB nuclear translocation-mediated lysosomal degradation of GPX4 promoting ferroptosis in trophoblast cells in pre-eclampsia (PubMed, Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi) - "In contrast, the cellular ferroptosis level was elevated in the hypoxia+si-TFEB+PP242 group. Conclusion Inhibition of TFEB nuclear translocation reduces ferroptosis in human embryonic trophoblast cells HTR8-S/Vneo, possibly by suppressing the lysosomal degradation of GPX4."

Journal • Gynecology • GPX4 • TFEB

mTOR inhibition promotes ATRA-induced cancer cell differentiation by overcoming a metabolic hyperactive state. (PubMed, J Transl Med) - "These findings uncover a conserved metabolic barrier that limits ATRA-induced differentiation beyond APL. mTOR acts as a critical node governing the balance between pro-differentiation and pro-metabolic signals. Co-targeting mTOR overcomes this barrier, particularly in RAS-mutant malignancies, providing a genotype-informed rationale for extending differentiation therapy to broader cancer contexts."

Journal • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Colon Cancer • Colorectal Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

In silico screening, synthesis, and biological evaluation of pyrazolopyrimidine-derived mTOR inhibitors for anticancer and senomorphic effects. (PubMed, Cancer Cell Int) - "Compound 5 demonstrates distinct biological effects compared to torkinib and represents a promising candidate for further development as an mTOR inhibitor targeting both cancer and senescent cells."

Journal • Brain Cancer • CNS Disorders • Diabetes • Glioblastoma • Glioma • Metabolic Disorders • Oncology • Solid Tumor • Type 2 Diabetes Mellitus • CXCL8 • IL6

The structure-activity relationship study of torkinib derivatives as mTOR inhibitors with senolytic and STAT3 inhibitory activities. (PubMed, Bioorg Chem) - "The mechanistic target of rapamycin (mTOR) sits at the center of several cellular pathways determining cell growth, function, and stress adaptation. Furthermore, compared to compound 4j, compound 4k exhibited cytotoxicity against both proliferating and senescent cells, comparable to torkinib despite its weaker TORC1 inhibition. In conclusion, our findings reveal structural alignments crucial for enhanced mTOR and STAT3 inhibition."

Journal • Oncology

High-content morphology profiling identifies autophagy-modulating compounds and their off-target activities (AACR 2026) - "The Cell Painting assay offers this possibility: by capturing rich morphological snapshots, it lets us see how different compounds alter organelles and pathways involved in autophagy. We exposed HepG2 cells for 24 hours to several well-characterized autophagy inhibitors—chloroquine, bafilomycin A1, dauricine, daurisoline, and dorsomorphine—as well as two established activators, rapamycin and PP242. Cell Painting proved effective at distinguishing autophagy-modulating compounds through their characteristic organelle-level effects. The unexpected behaviour of MCOPPB highlights a previously overlooked mechanism. Combining morphological profiling with marker-based validation provides a practical framework for identifying new modulators of autophagy with potential oncological relevance.This work was supported by the Technology Agency of the Czech Republic project PERMED: T2BA (TN02000109)."

Oncology • SQSTM1

Zongertinib-tolerant cells enhanced sensitivity to Topo1 inhibition in Her2-positive NCSLC (AACR 2026) - "For the treatment of Her2 mutated/amplified NSCLC, the antibody-drug conjugate Trastuzumab deruxtecan, several Her2-selective inhibitors, such as zongertinib and sevabertinib, have shown beneficial efficacy in clinical settings...Drug screening revealed that zongerR cells exhibited sensitivity to the multi-tyrosine kinase inhibitor ponatinib and foretinib. Additionally, PI3K/AKT pathway inhibitors (PI3Ki) such as GDC0941 and mTOR inhibitor PP242 also markedly suppressed the survival of zongerR cells in combination with zongertinib...Currently, zongertinib and T-Dxd have been approved for Her2-positive NSCLC, whereas treatment strategies to prolong the durable response have not been well-established. Further investigations were needed, but our findings suggested that T-DXd treatment after zongertinib may be a potential therapeutic strategy in a subset of Her2-positive NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

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

Tolerogenic dendritic cells induced by withdrawal of polyunsaturated fatty acid DHA and mTOR inhibitor PP242 attenuate allograft rejection. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "Adoptive transfer of comb-DHA-DCs suppresses allograft rejection reactions. In summary, our findings reveal a novel strategy for inducing Tol-DCs and present a promising therapeutic avenue for enhancing graft tolerance."

Journal • Transplant Rejection • Transplantation • PTDSS2

Stomatal closing compounds dissect the signaling pathway for light-induced stomatal opening and confer drought tolerance in plants. (PubMed, Plant Cell Physiol) - "These results imply that SCL10 inhibits blue-light-induced phosphorylation of Thr948 and stomatal opening upstream of the site of action of PP242, whereas SCL11 inhibits the phosphorylation of both Thr948 and Thr881, and acts downstream of the site of action of PP242. Finally, the compounds were sprayed onto rose leaves, and we observed that wilting was suppressed only in leaves sprayed with SCL10, for up to 5 h."

Journal

In Vitro Inhibition of Cryptosporidium parvum Infection by the Olive Oil Component Oleocanthal. (PubMed, Pathogens) - "The principal involvement of mTOR in C. parvum inhibition was confirmed by another mTOR-inhibitor (PP242, 0.5 µM), which also reduced C. parvum infection by 70-77%. Given that oleocanthal is not a selective mTOR inhibitor, we assume that this compound drives a multi-target-based inhibition of asexual C. parvum replication, amongst which mTOR is addressed."

Journal • Preclinical • Infectious Disease

Targeting mTOR Kinase for Cancer Treatment: A Comprehensive Review With Clinical Insights. (PubMed, Drug Dev Res) - "Key mTOR inhibitors, including rapalogs (e.g., sirolimus, everolimus) and ATP-competitive inhibitors (e.g., MLN0128, PP242), are discussed in detail, along with their clinical applications and limitations. Additionally, we summarize the findings from major clinical trials, including FDA-approved mTOR inhibitors like everolimus and temsirolimus, and non-FDA-approved inhibitors such as sapanisertib and ridaforolimus. The review underscores the importance of understanding mTOR signaling and its role in cancer progression, offering insights into the future of mTOR-targeted therapies in oncology."

Journal • Review • Genito-urinary Cancer • Hematological Malignancies • Multiple Myeloma • Oncology • Renal Cell Carcinoma • Solid Tumor

Changes in Melanoma Cell Morphology Following Inhibition of Cell Invasion by Third-Generation mTOR Kinase Inhibitors. (PubMed, Int J Mol Sci) - "The study used mTOR kinase inhibitors: Everolimus and Torkinib; dual PI3K/mTOR inhibitors BEZ-235 and Omipalisib; and the mTORC1/2 inhibitor OSI-027. These compounds were used both as monotherapy and in combination with the MEK1/2 inhibitor AS-703026...The morphology of cells also changed significantly: their thickness, volume, roughness, convexity of shape, and irregularity, which may be a good diagnostic and prognostic factor for the response to treatment. Our studies to date on the effect of three generations of mTOR kinase inhibitors on the inhibition of the invasion process, the activation of apoptosis, and the reduction in cell proliferation suggest that they may be an important target for anticancer therapy."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • MMP2 • MMP9

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

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

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