RapaLink-1 / University of California, Revolution Medicines - LARVOL DELTA

CD36-mediated endocytosis of proteolysis-targeting chimeras. (PubMed, Cell) - "Here, using biotinylated chemical-probe-based target fishing and genetic knockdown/knockin approaches, we discovered that the membrane cluster of differentiation 36 (CD36) binds to and facilitates the uptake and efficacy of diverse PROTACs (e.g., SIM1-Me, MZ1, and clinical ARV-110) and large and/or polar small-molecule drugs (e.g., rapalink-1, rapamycin, navitoclax, birinapant, tubacin, and doxorubicin) via the CD36-mediated early endosome antigen 1 (EEA1)/Ras-related protein 5A (Rab5) endosomal cascade in vitro and/or in vivo. We then devised a novel chemical endocytic medicinal chemistry strategy to improve binding of PROTACs to CD36 using structural modifications via the prodrug approach, markedly enhancing PROTAC anti-tumor efficacy through spontaneously augmenting permeability and solubility."

Journal • Oncology • Targeted Protein Degradation • CD36 • RAB5A • SCARB1

mTOR Inhibitor Rapalink-1 Prevents Ethanol-Induced Senescence in Endothelial Cells. (PubMed, Cells) - "Rapalink-1 also reduced the relative protein expression of MMP-2. In summary, Rapalink-1 prevented senescence, inhibited pro-inflammatory pathway activation, and ameliorated pro-inflammatory molecule expression and MMP-2."

Journal • Cardiovascular • Inflammation • CDKN1A • CXCL8 • ICAM1 • MMP2 • TIMP2

RapaLink-1 outperforms rapamycin in alleviating allogeneic graft rejection by inhibiting the mTORC1-4E-BP1 pathway in mice. (PubMed, Int Immunopharmacol) - "Mechanistically, the ameliorated rejection induced by RapaLink-1 is associated with a reduction in p-4E-BP1 in T cells, resulting in an elevation in Treg cells alongside a decline in Th1 and Th17 cells. For the first time, these studies demonstrate the effectiveness of third-generation mTOR inhibitors in inhibiting allograft rejection, highlighting the potential of this novel class of mTOR inhibitors for further investigation."

Journal • Preclinical • Transplant Rejection • Transplantation • EIF4EBP1

In Vitro Delivery of mTOR inhibitors by Kidney-Targeted Micelles for Autosomal Dominant Polycystic Kidney Disease. (PubMed, SLAS Technol) - "However, mTOR inhibitors, including rapamycin, everolimus, and RapaLink-1, have off-target side effects including immunosuppression. These results indicate that PAM encapsulation is a promising way to deliver mTOR inhibitors to CCD cells and potentially treat ADPKD. Future studies will evaluate the therapeutic effect of PAM-drug formulations and ability to prevent off-target side effects associated with mTOR inhibitors in mouse models of ADPKD."

Journal • Preclinical • Autosomal Dominant Polycystic Kidney Disease • Chronic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

eIF4A1 Is a Prognostic Marker and Actionable Target in Human Hepatocellular Carcinoma. (PubMed, Int J Mol Sci) - "Significantly, anti-growth effects were achieved at nanomolar concentrations of the eIF4A1 inhibitors and were further increased by the simultaneous administration of the pan mTOR inhibitor, Rapalink-1. In conclusion, our results highlight the pathogenetic relevance of eIF4A1 in HCC and recommend further evaluation of the potential usefulness of pharmacological combinations based on eIF4A and mTOR inhibitors in treating this aggressive tumor."

Biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Transplantation • EIF4A1

IFITM proteins assist cellular uptake of diverse linked chemotypes. (PubMed, Science) - "Using complementary genome-scale chemical-genetic approaches we identified an endogenous chemical uptake pathway involving interferon-induced transmembrane proteins (IFITMs) that modulates the cell permeability of a prototypical biopic inhibitor of MTOR (RapaLink-1, MW: 1784 g/mol). We devised additional linked inhibitors targeting BCR-ABL1 (DasatiLink-1, MW: 1518 g/mol) and EIF4A1 (BisRoc-1, MW: 1466 g/mol), uptake of which was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis-targeting chimeras and examined the physicochemical requirements for involvement of this uptake pathway."

Journal • Targeted Protein Degradation • ABL1 • BCR • EIF4A1

Brain-restricted mTOR inhibition with binary pharmacology. (PubMed, Nature) - "Here we report a strategy to achieve inhibition of mammalian target of rapamycin (mTOR) while sparing mTOR activity elsewhere through the use of the brain-permeable mTOR inhibitor RapaLink-1 and the brain-impermeable FKBP12 ligand RapaBlock...We further present a general method to design cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds. These inhibitors are sensitive to deactivation by RapaBlock, enabling the brain-restricted inhibition of their respective kinase targets."

Journal • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Solid Tumor

mTORC1 and mTORC2 Complexes Regulate the Untargeted Metabolomics and Amino Acid Metabolites Profile through Mitochondrial Bioenergetic Functions in Pancreatic Beta Cells. (PubMed, Nutrients) - "Dual mTORC1/mTORC2 inhibition by RapaLink-1 and Torin-2 differentially altered the amino acid profile and decreased mitochondrial respiration compared to rapamycin treatment which only blocks the FRB domain on mTOR. Third-generation mTOR inhibitors may alter the mitochondrial dynamics and reveal a bioenergetics profile that could be targeted to reduce mitochondrial stress."

Journal

AR and mTOR signaling regulates tumor growth and survival in vivo in advanced prostate cancer models (EACR 2022) - "We treated both models in vivo and in vitro with combinations of ADT and Rapalink-1; a new generation mTOR inhibitor, to evaluate the effect of combined AR and mTOR signaling blockade on PCa tumor growth and cytological characteristics...Conclusion While the hormone-sensitive BM18 model requires both AR and mTOR signaling for growing, growth of the CRPC model LAPC9 requires only one of the two pathways to be active. mTOR blockade moreover had an impact on AR signaling, as evidenced by altered AR localization in treated samples."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD44

First, second, and third generation mTOR pathways inhibitors for treatment of glioblastoma (AACR 2022) - "These results suggested that RAPA, Torin1, Torin2, and Rapalink-1, but not XL388, are useful in suppressing the mTORC1 and mTORC2 activities, thereby inhibiting GB cell proliferation, dissemination, and inhibiting stem cell self-renewal. Therefore, the use of these mTOR inhibitors presents a promising treatment strategy for Glioblastoma."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • AKT1S1 • EIF4EBP1 • NES • PTEN

Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma. (PubMed, Adv Biol Regul) - "Since rapamycin and it's analogue are less effective in treatment of GB, we used novel ATP-competitive dual inhibitors of mTORC1 and mTORC2, namely, Torin1, Torin2, and XL388. In addition, formulation of third generation mTOR inhibitor "Rapalink-1" may provide new aspects to target mTOR pathways. Numerous inhibitors are currently being used in clinical trials that are aimed to target activated mTOR pathways."

Journal • Review • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • AKT1S1 • EIF4EBP1 • PTEN

[VIRTUAL] Rapalink-1 Increased Infarct Size And Blood-brain Barrier Disruption In Early Cerebral Ischemia-reperfusion (ASA 2021) - "MethodsMiddle cerebral artery occlusion (MCAO) was performed in rats under isoflurane anesthesia with controlled ventilation. ConclusionOur data demonstrate that inhibition of both mTORC1 and mTORC2 by Rapalink-1 increased the size of the cortical infarct in the ischemic-reperfused cortex with an increase in BBB disruption. Our data suggest that dual inhibition of mTORC1 and mTORC2 could aggravate neuronal damage in the very early stage of cerebral ischemia-reperfusion which is within the thrombolysis therapy time window and that increased BBB disruption could be one of the contributing factors."

Anesthesia • Ischemic stroke • Reperfusion Injury • MMP2

Rapalink-1 Increased Infarct Size And Blood-brain Barrier Disruption In Early Cerebral Ischemia-reperfusion (ASA 2021) - "MethodsMiddle cerebral artery occlusion (MCAO) was performed in rats under isoflurane anesthesia with controlled ventilation. ConclusionOur data demonstrate that inhibition of both mTORC1 and mTORC2 by Rapalink-1 increased the size of the cortical infarct in the ischemic-reperfused cortex with an increase in BBB disruption. Our data suggest that dual inhibition of mTORC1 and mTORC2 could aggravate neuronal damage in the very early stage of cerebral ischemia-reperfusion which is within the thrombolysis therapy time window and that increased BBB disruption could be one of the contributing factors."

Anesthesia • Ischemic stroke • Reperfusion Injury • MMP2

Commentary: Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia-Reperfusion With Increased Blood-Brain Barrier Disruption. (PubMed, Front Physiol) - No abstract available

Journal • Cardiovascular • Reperfusion Injury

Rapalink-1 and Hydroxychloroquine Exhibit an Additive Effect in Undifferentiated Pleomorphic Sarcoma by Inducing Apoptosis. (PubMed, Anticancer Res) - "Combined treatment with Rapalink-1 and hydroxychloroquine may be used as a potential therapeutic agent against UPS."

Journal • Oncology • Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma

CONSEQUENCES OF mTOR INHIBITION ON AAV HEPATIC TRANSDUCTION EFFICACY. (PubMed, Hum Gene Ther) - "In this study, we explored the results of AAV hepatic transduction when different mTOR inhibitors.- rapamycin, MLN0128, RapaLink-1 -were used in preconditioned juvenile and adult mice. Therefore, our results show a complex interaction between the mTOR pathway and AAV-mediated hepatic transduction and indicate that mTOR inhibition is not a straightforward strategy for improving AAV transduction. More studies are necessary to elucidate the molecular mechanisms involve in the positive and negative effects of mTOR inhibitors on AAV transduction efficiency."

Clinical • Journal

Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia-Reperfusion With Increased Blood-Brain Barrier Disruption. (PubMed, Front Physiol) - "The middle cerebral artery occlusion (MCAO) was performed in rats under isoflurane anesthesia with controlled ventilation. The MMP2 level was increased suggesting that BBB disruption could be aggravated by Rapalink-1. Taken together, our data suggest that inhibiting both mTORC1 and mTORC2 by Rapalink-1 could worsen the neuronal damage in the early stage of cerebral ischemia-reperfusion and that the aggravation of BBB disruption could be one of the contributing factors."

Journal • Anesthesia • Reperfusion Injury • MMP2

Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice. (PubMed, Nat Commun) - "RapaBlock also prevented the adverse side effects produced by chronic inhibition of mTORC1. Importantly, co-administration of RapaLink-1 and RapaBlock inhibited alcohol-dependent mTORC1 activation in the nucleus accumbens and attenuated alcohol seeking and drinking."

Adverse events • Journal • Preclinical • Addiction (Opioid and Alcohol)

Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide. (PubMed, Cancers (Basel)) - "We supported the in silico results with correlative protein data retrieved from tumor specimens. Our study further validates mTOR signaling as a druggable target in GBM and supports RL1, representing a promising therapeutic target in brain oncology."

Journal • Glioblastoma • Oncology • Solid Tumor

RapaLink-1 plays an antithrombotic role in antiphospholipid syndrome by improving autophagy both in vivo and vitro. (PubMed, Biochem Biophys Res Commun) - "Our results revealed that Rapalink-1 has a potential to inhibit the formation of thrombus plaque in APS and these effects were dependent on facilitating cell autophagy both in vivo and in vitro."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Genetic Disorders • Hematological Disorders • Thrombosis

[VIRTUAL] Mechanistic Target of Rapamycin, but Not the Integrated Stress Response, Promotes ATF4-Dependent Metabolic Reprogramming in TGF-β-Treated Lung Fibroblasts (ATS-I 2020) - "mTOR was inhibited chemically using Rapalink-1. ATF4 is required for TGF-β-induced expression of the enzymes of the de novo serine-glycine synthesis pathway as well as for collagen protein production. TGF-β-induced activation of mTOR, but not the ISR is required for ATF4 induction. While mTOR inhibition prevented collagen protein production similar to ATF4 knockdown, inhibition of the ISR increased collagen production."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • EIF4EBP1 • mTOR • PSAT1

[VIRTUAL] Potential new therapy against sunitinib-resistant renal cell carcinoma (AUA 2020) - "Introduction: Temsirolimus and Everolimus, termed rapalogs, have been used as first generation mTOR inhibitors for renal cell carcinoma (RCC)...Recently third generation mTOR inhibitor Rapalink-1, which was designed to have combinational functions between Rapamycin and TORKi, had been developed with therapeutic effectiveness against mTOR resistance mutations in breast cancer cells (Nature, 2016)... It was found that Rapalink-1 had superior therapeutic effects to Temsirolimus in SU-R-RCC cells as well as the parent RCC cells. Our study suggests a potential new option for the treatment of patients with RCC who have acquired resistance to conventional molecular targeted drugs. Source of Funding: None"

Breast Cancer • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EIF4EBP1

Potential new therapy of Rapalink-1, a new generation mTOR inhibitor, against sunitinib-resistant renal cell carcinoma. (PubMed, Cancer Sci) - "Recently, Rapalink-1, a drug that links rapamycin and the mTOR kinase inhibitor MLN0128, has been developed with excellent therapeutic effects against breast cancer cells carrying mTOR resistance mutations. The aim of the present study was to evaluate the in vitro and in vivo therapeutic efficacy of Rapalink-1 against renal cell carcinoma (RCC) compared to temsirolimus, which is commonly used as a small molecule inhibitor of mTOR and is a derivative of rapamycin...RNA sequencing showed that Rapalink-1 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters that were associated with resistance to several drugs. Our study suggests the possibility of a new treatment option in the treatment of patients with RCC that is either sunitinib-sensitive or -resistant."

Journal • Breast Cancer • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity. (PubMed, Front Oncol) - "Exposure of LAPC9 to Rapalink-1 but not to the CSC-targeting drug disulfiram blocked mTORC1/2 signaling, diminished expression of metabolic enzymes involved in glutamine and lipid metabolism and reduced the fraction of CD44 and ALDEFluor cells, in vitro. Mice treated with Rapalink-1 showed a significantly delayed tumor growth compared to control and cells recovered from the tumors of treated animals showed a marked decrease of CD44 expression. Taken together these results highlight the increased dependence of advanced PCa on the mTOR pathway, supporting the development of a targeted approach for advanced, bone metastatic PCa."

Clinical • Heterogeneity • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CD44

TGF-β Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation. (PubMed, Am J Respir Cell Mol Biol) - "Rapamycin, which incompletely and allosterically inhibits mTORC1 had no effect on TGF-β-mediated induction of ATF4; however, Rapalink-1, which specifically targets the kinase domain of mTORC1 completely inhibited ATF4 induction and metabolic reprogramming downstream of TGF-β. Our results provide insight into the mechanisms of metabolic reprogramming in myofibroblasts and clarify contradictory published findings on the role of mTOR inhibition in myofibroblast differentiation."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases