MRT68921 / University of Dundee - LARVOL DELTA

Bitopic inhibitors of mTORC1 cooperate with inhibitors of mitogen-activated protein kinase kinase to drive cytotoxicity in glioblastoma. (SNO 2025) - "We previously described RapaLink-1, a bisteric mTORC1 inhibitor that links the allosteric mTORC1 inhibitor rapamycin to the mTOR kinase inhibitor sapanisertib...Like trametinib, the MEK inhibitor selumetinib similarly cooperated with RMC-6272 to block proliferation and increase apoptosis in isogenic T98G glioblastoma lines knocked-down for NF1 compared to NF1 wild-type T98G cells...Combining RMC-6272, trametinib and the autophagy ULK1 tool inhibitor MRT68921 augmented apoptosis compared to RMC-6272 and trametinib alone...We conclude that bitopic inhibitors of mTORC1 cooperate with inhibitors of MEK to drive cytotoxicity in both NF1WT and NF1MT glioblastoma. Combining RMC-5552 and trametinib represents a translatable strategy to improve survival in patients with glioblastoma."

Brain Cancer • Glioblastoma • Solid Tumor • NF1

Bitopic inhibitors of mTORC1 cooperate with inhibitors of mitogen-activated protein kinase kinase to drive cytotoxicity in glioblastoma. (WFNOS 2025) - "We previously described RapaLink-1, a bisteric mTORC1 inhibitor that links the allosteric mTORC1 inhibitor rapamycin to the mTOR kinase inhibitor sapanisertib...Like trametinib, the MEK inhibitor selumetinib similarly cooperated with RMC-6272 to block proliferation and increase apoptosis in isogenic T98G glioblastoma lines knocked-down for NF1 compared to NF1 wild-type T98G cells...Combining RMC-6272, trametinib and the autophagy ULK1 tool inhibitor MRT68921 augmented apoptosis compared to RMC-6272 and trametinib alone...We conclude that bitopic inhibitors of mTORC1 cooperate with inhibitors of MEK to drive cytotoxicity in both NF1WT and NF1MT glioblastoma. Combining RMC-5552 and trametinib represents a translatable strategy to improve survival in patients with glioblastoma."

Brain Cancer • Glioblastoma • Solid Tumor • NF1

T-Lymphocyte Suppression By ULK2 High Expression of CD14+ Monocytes in Patients with Multiple Myeloma (ASH 2024) - "The protein levels of MHC Ⅰ, TAP1, PSME1, MHC Ⅱ, CTSB, CTSL, and the MFI of CD86 in oeULK2 THP1 was upregulated accompanying with various concentrations of ULK1/ULK2 inhibitor (MRT68921) co-culture for 48h...This disruption affects T-lymphocyte activation and attenuates their ability to kill and secrete cytokines. This study provides a theoretical basis for understanding the formation of the myeloma immunosuppressive microenvironment, enhancing the efficacy of T lymphocyte-based immunotherapy, and developing new targeted therapies ULK2."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CD14 • CD69 • CD80 • CD86 • GLI2 • GZMB • HLA-DQB1 • IFNG • PSME1 • TAP1 • TNFA • ULK2

Polycomb Repressive Complex 2 Regulates Differentiation-Stage-Specific Autophagy Gene Expression and Safeguards Normal Erythropoiesis (ASH 2024) - "Interestingly,β-Est treatment, thus maturation of G1ER cells, rendered cells resistant to rapamycin or trehalose -induced cell death and proliferation inhibition, suggesting that prematurely increased autophagy activity in early erythroid precursors leads to cell death and reduced proliferation...This is consistent with the premature elevation of enucleation-related genes in Ezh2 KO mice, such as Riok3, E2f2 and others.Erythropoiesis defects in Ezh2 KO mice can be partly rescued by the administration of chloroquine or the ULK1 inhibitor MRT68921...Deregulated autophagy gene expression in Ezh2 KO mice leads to reduced cell proliferation and increased apoptosis in R2 and R3 cells, as well as premature enucleation and organelle clearance in late precursors. Collectively, these factors lead to insufficient expansion of erythroid precursor cells and poorly prepared mature cells for oxygen carrying, resulting in severe anemia in Ezh2 KO mice."

Anemia • Hematological Disorders • E2F2 • EZH2 • GATA1 • MAP1LC3B • PIK3R1 • TFRC

Lumpy Skin Disease Virus Strategically Modulates Autophagy to Facilitate Viral Replication in MDBK Cells. (PubMed, Microb Pathog) - "Pharmacological modulation of autophagy using activators (Rapamycin, Torin 2) and inhibitors (Bafilomycin A1, MRT68921) revealed that increased autophagy enhanced LSDV replication, whereas inhibition of autophagy significantly impaired viral propagation, underscoring the virus's reliance on autophagic processes for efficient replication. These findings suggest that LSDV strategically modulates autophagy by maintaining basal autophagic levels while suppressing lysosomal degradation, allowing for optimal viral replication. Understanding the interplay between LSDV and autophagy provides novel insights into its pathogenesis and identifies potential antiviral targets to mitigate LSDV infections in cattle."

Journal • Dermatology • Infectious Disease • LAMP2

ULK2 deficiency stratifies autophagy-driven molecular subtypes and exacerbates trophoblasts apoptosis in preeclampsia. (PubMed, Placenta) - "ULK2 deficiency disrupts trophoblast homeostasis, driving placental dysfunction and severe clinical outcomes. The ULK2low subtype highlights autophagy heterogeneity in PE. While pharmacological ULK2 inhibition recapitulates PE in mice, limitations include sample size and MRT68921's dual ULK1/2 activity. Our findings propose ULK2 agonism as novel therapeutic strategies."

Journal • Cardiovascular • Gynecology • Hypertension • Renal Disease • ULK2

Inhibition of Unc-51-like-kinase is mitoprotective during Pseudomonas aeruginosa infection in corneal epithelial cells. (PubMed, mSphere) - "Using a standard invasive test strain of PA, we show that PA infection triggers dephosphorylation of the mechanistic target of rapamycin in corneal epithelial cells, leading to the induction of autophagy through ULK1/2...Treatment with the ULK1/2 inhibitor, MRT68921, which blocks phagophore formation, attenuated levels of intracellular PA in corneal epithelial cells...This leads to a reduction in intracellular levels of PA and changes in the inflammatory milieu. Together, these data suggest that the inhibition of ULK1/2 may be mitoprotective in corneal epithelial cells during PA infection."

Journal • Infectious Disease • Ocular Infections • Ophthalmology • CXCL8 • IL6 • mTOR

Novel combinatorial autophagy inhibition therapy for triple negative breast cancers. (PubMed, Eur J Pharmacol) - "In this study, a novel combination between different autophagy inhibitors was identified which inhibited tumor cell proliferation in both chemosensitive and chemoresistant TNBC cells and could result in development of novel treatment modality against TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EGF • HER-2

ULK2 Is a Key Pro-Autophagy Protein That Contributes to the High Chemoresistance and Disease Relapse in FLT3-Mutated Acute Myeloid Leukemia. (PubMed, Int J Mol Sci) - "Furthermore, chloroquine (an autophagy inhibitor) sensitized SORE6 but not SORE6 cells to Ara-C...MRT68921 significantly sensitized SORE6 but not SORE6 cells to Ara-C...Lastly, using pretreatment and relapsed AML patient bone marrow samples, we found that ULK2 expression was higher in relapsed AML. To conclude, our results supported the importance of autophagy in the relapse of FLT3-mutated AML and highlighted ULK2 in this context."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • ULK2

Inhibition of autophagy initiation: A novel strategy for oral squamous cell carcinomas. (PubMed, Biochim Biophys Acta Mol Cell Res) - "In conclusion, this study identified a combination of novel autophagy inhibitors which can potently inhibit proliferation of both chemosensitive as well as chemoresistant OSCC cells and could be developed as a novel therapy against advanced OSCC tumors."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • TGM2

The Effects of Cinobufagin on Hepatocellular Carcinoma Cells Enhanced by MRT68921, an Autophagy Inhibitor. (PubMed, Am J Chin Med) - "In addition, the autophagy inhibitor MRT68921 improved the antiproliferative and proapoptotic effects of cinobufagin in the studied cell lines. Overall, this study suggests that combining cinobufagin with an autophagy inhibitor can effectively treat HCC, providing a potential strategy for cancer therapy."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • BECN1

Evaluation of the Effectiveness of Various Autophagy Inhibitors in A549 Cancer Stem Cells. (PubMed, Acta Naturae) - "In the present work, we selected a panel of autophagy inhibitors (Autophinib, SBI-0206965, Siramesine, MRT68921, and IITZ-01), some of whom have been recently identified as effective autophagy inhibitors in cancer cells...Moreover, Autophinib-treated A549 cells are unable to form spheroids, which indicates a reduction in stemness. Thus, among the drugs studied, only Autophinib can be considered a potential agent against cancer stem cells."

Cancer stem • Journal • Oncology • POU5F1 • SOX2

ULK1 Blockade Preferentially Targets Germinal Centre B-Cell – Diffuse Large B-Cell Lymphoma Subtype By Attenuating Autophagy, c-MYC and Inflammation (ASH 2022) - "Addition of ULK1 complex inhibitor (MRT68921) augmented the anti-tumor activity of Ibrutinib in HT, Oci-Ly1, Oci-Ly18 and SUDHL-6 GCB cell lines and activated caspase dependent apoptosis...Younes, A., et al., Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma...Davies, A., et al., Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol, 2019. 20(5): p. 649-662."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immunology • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • AMBRA1 • CD79B • IL6 • MYC • MYD88 • PIK3C3 • PTEN • RB1CC1

Inhibition of mTOR signaling protects human glioma cells from hypoxia-induced cell death in an autophagy-independent manner. (PubMed, Cell Death Discov) - "We analyzed autophagic activity, cell growth, viability and oxygen consumption following (co-)treatment with the mTOR inhibitors torin2 or rapamycin, and autophagy inhibitors bafilomycin A1 or MRT68921...Our proteomic findings suggest that the pharmacological inhibition of autophagy induces extensive changes in the cellular proteome that can support glioma cell survival under nutrient-deplete and hypoxic conditions. These findings provide a novel perspective on the complex role of autophagy in gliomas."

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

STAT3 suppresses the AMPKα/ULK1-dependent induction of autophagy in glioblastoma cells. (PubMed, J Cell Mol Med) - "Inhibition of ULK1 activity (by treatment with MRT68921) or its expression (by siRNA knockdown) in STAT3-KO cells inhibits autophagy and sensitizes cells to apoptosis. Taken together, our findings suggest that serine and tyrosine phosphorylation of STAT3 play critical roles in STAT3-dependent autophagy in GBM, and thus are potential targets to treat GBM."

Journal • Brain Cancer • Glioblastoma • Oncology • Pediatrics • Solid Tumor • CTSD • STAT3 • TSC2