trodulamine (MSI-1436) / Novo Biosci - LARVOL DELTA

TRODUSQUEMINE PREVENTS THE FORMATION OF TDP -43 INCLUSIONS AND THEIR ASSOCIATED NEUROTOXICITY (ADPD 2025) - "This study provides evidence that TRO can prevent the pathological effects induced by TDP - 43, putting forwards its potential as a new the rapeutic candidate in TDP -43-associated proteinopathies."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Movement Disorders • Parkinson's Disease • Proteinopathy

Natural aminosterols inhibit NMDA receptors with low nanomolar potency. (PubMed, FEBS J) - "Fluorescence resonance energy transfer (FRET) measurements using labeled NMDAR and the labeled aminosterol trodusquemine (TRO) indicate close spatial proximity, likely arising from binding...Inhibition is observed only after cell membrane pre-adsorption, indicating accessibility to NMDAR from the cell membrane and binding to the transmembrane domains (TMDs) and TMD-ligand-binding domain (LBD) linkers, similarly to PAS. The TRO IC50 is 5000-fold higher than that of PAS and 20-16 000 times higher than those of other inhibitors binding to TMD/TMD-LBD regions, identifying aminosterols as promising and potent NMDAR modulators."

Journal • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Pharmacological PTP1B inhibition rescues motor learning, neuroinflammation, and hyperglycaemia in a mouse model of Alzheimer's disease. (PubMed, Exp Neurol) - "We provide evidence that neuronal BACE1 contributes to neuroinflammation and hyperglycaemia in PLB4 mice, and this can be partially rescued by PTP1B inhibition. Targeting PTP1B may therefore offer an attractive therapeutic approach to ameliorate co-morbidity associated pathologies in AD and T2DM."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Diabetes • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • APP • HSPA5 • IGH • IRS1 • PTPN1

A novel, centrally acting mammalian aminosterol, ENT-03, induces weight loss in obese and lean rodents. (PubMed, Diabetes Obes Metab) - "These data support a role for ENT-03 in the treatment of type 2 diabetes and obesity. Phase 1 studies in subjects with obesity and diabetes are currently in progress."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Natural products targeting amyloid-β oligomer neurotoxicity in Alzheimer's disease. (PubMed, Eur J Med Chem) - "In this review, we explore the role of NPs in mitigating AβO neurotoxicity for AD drug discovery, summarizing key evidence from biophysical methods, cellular assays, and animal models. By discussing how NPs modulate AβO neurotoxicity across various experimental systems, we aim to provide valuable insights into novel therapeutic strategies targeting AβOs in AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Combination of microparticles vaccine with MSI-1436 exerts a strong immune response for hepatocellular carcinoma. (PubMed, J Leukoc Biol) - "Overall, MPs combined with MSI-1436 exerted stronger anti-tumor effects than MPs or MSI-1436 alone. Therefore, the combination of MPs and MSI-1436 may be a promising means of treating HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD4 • CD8 • PTPN1 • TNFA

Leveraging Machine Learning-Guided Molecular Simulations Coupled with Experimental Data to Decipher Membrane Binding Mechanisms of Aminosterols. (PubMed, J Chem Theory Comput) - "In this work, we leverage the Time-lagged Independent Component Analysis (TICA) in combination with neural networks (NN) through the Deep-TICA approach for determining the free energy associated with the membrane insertion processes of two natural aminosterol compounds, trodusquemine (TRO), and squalamine (SQ)...The findings contribute significantly to our understanding of aminosterol entry pathways and aminosterol-lipid membrane interactions. Finally, the computational methods deployed in this study further demonstrate considerable potential for investigating membrane binding processes."

Journal • Machine learning • CNS Disorders

A Review of the Protective Effects of Alkaloids Against Alpha-synuclein toxicity in Parkinson's disease. (PubMed, Mini Rev Med Chem) - "The findings of the present study highlight the inhibitory activities of alkaloids against synucleinopathy. However, no clinical data supports the reported activities in humans, which calls attention to the need for conducting clinical trials to elucidate the efficacy, safety, proper dosage, unwanted effects and pharmacokinetics aspects of alkaloids in humans."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease

Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations. (PubMed, Aging Cell) - "In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life."

Journal • Preclinical • Diabetes • Dyslipidemia • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • LEP • mTOR • PTPN1

Overexpression of forebrain PTP1B leads to synaptic and cognitive impairments in obesity. (PubMed, Brain Behav Immun) - "Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-1436, well-tolerated in Phase 1 and 1b clinical trials for obesity and type II diabetes) prevented these alterations, including improving cognition, neurite outgrowth, leptin synaptic signaling and BDNF in both obese cognitive impairment mice and a neural cell model of PTP1B overexpression. These findings suggest that increased forebrain PTP1B is associated with cognitive decline in obesity, whereas inhibition of PTP1B could be a promising strategy for preventing neurodegeneration induced by obesity."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Diabetes • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • LEP • LEPR • PTPN1

Trodusquemine (MSI-1436) Restores Metabolic Flexibility and Mitochondrial Dynamics in Insulin-Resistant Equine Hepatic Progenitor Cells (HPCs). (PubMed, Cells) - "It also promotes mitochondrial dynamics by modulating mitochondria quantity and morphotype as well as increasing the expression of PINK1, MFN1, and MFN2. Our study provides evidence that MSI-1436 has a positive impact on equine hepatic progenitor cells, indicating its potential therapeutic value in treating EMS and insulin dysregulation."

Journal • Metabolic Disorders • MFN1 • MFN2 • PINK1 • PTPN1 • SIRT1

Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism. (PubMed, J Transl Med) - "Overall, these results suggest that myeloid-PTP1B inhibition has atheroprotective effects through improved cholesterol handling in atherosclerotic lesions, as well as increased reverse cholesterol transport. Trial registration Research registry, researchregistry 3235. Registered 07 November 2017, https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5a01d0fce7e1904e93e0aac5/ ."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • AMPK • APOB • APOE • GLI2 • IL10 • PTPN1

The PTP1B Inhibitor Trodusquemine (MSI-1436) Improves Glucose Uptake in Equine Metabolic Syndrome Affected Liver through Anti-Inflammatory and Antifibrotic Activity. (PubMed, Int J Inflam) - "Furthermore, application of MSI-1436 was found to augment the abundance of glycosylated Glut-2, which subsequently expanded the glucose absorption in the EMS liver, probably due to an enhanced Glut-2 stability and half-life onto the plasma cell membranes. Taken together, the presented data suggest that the PTP1B inhibition strategy and the use of its specific inhibitor MSI-1436 represents a promising option for the improvement of liver tissue integrity and homeostasis in the course of EMS and adds more insights for ongoing clinical trials for human MetS management."

Journal • Diabetes • Endocrine Disorders • Fibrosis • Immunology • Inflammation • Metabolic Disorders • IL10 • IL1B • IL4 • IL6 • MIR211 • MMP2 • MMP9 • PTPN1 • SMAD7 • TGFB1 • TIMP1 • TNFA

Medicinal Aspects of PTP 1B Inhibitors as Anti-Breast Cancer Agents: An Overview. (PubMed, Curr Med Chem) - "ertiprotafib and trodusquemine, have entered clinical trials...In this review, we provide an extensive overview on the involvement of PTP1B in breast cancer, its pathophysiology, with special attention on the discovery and development of various natural as well as synthetic PTP1B inhibitors. This study will provide significant information to the researchers developing PTP1B inhibitors for breast cancer treatment."

Journal • Breast Cancer • Diabetes • Genetic Disorders • HER2 Breast Cancer • Metabolic Disorders • Obesity • Oncology • Solid Tumor • Type 2 Diabetes Mellitus • HER-2 • PTPN1

Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine. (PubMed, Int J Mol Sci) - "In this review article, we provide an overview of the main findings regarding the activities and therapeutic potential of trodusquemine and their correlation with PTP1B inhibition. We also included some aminosterol analogues and related structure-activity relationships that could be useful for further studies aimed at the discovery of new allosteric PTP1B inhibitors."

Journal • Review • CNS Disorders • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Oncology • PTPN1

6-Polyaminosteroid Squalamine Analogues Display Antibacterial Activity against Resistant Pathogens. (PubMed, Int J Mol Sci) - "A series of 6-polyaminosteroid analogues of squalamine were synthesized with moderate to good yields and evaluated for their in vitro antimicrobial properties against both susceptible and resistant Gram-positive (vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus) and Gram-negative (carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa) bacterial strains. On the other hand, the derivative 4f, which carries a spermine moiety like that of the natural trodusquemine molecule, was found to be the most active derivative against all the resistant Gram-negative bacteria tested, with an MIC value of 16 µg/mL. Our results suggest that 6-polyaminosteroid analogues of squalamine are interesting candidates for Gram-positive bacterial infection treatments, as well as potent adjuvants to fight Gram-negative bacterial resistance."

Journal • Infectious Disease

The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses. (PubMed, Front Endocrinol (Lausanne)) - "Interestingly, inhibition of PTP1B resulted in potent attenuation of ER stress key mediators' expression namely, CHOP, ATF6, HSPA5 and XBP1. Presented findings shed for the first time promising new insights in the development of an MSI-1436-based therapy for proper equine metabolic syndrome intervention and may additionally find potential translational application to human metabolic syndrome treatment."

Journal • Diabetes • Inflammation • Metabolic Disorders • ATF6 • BECN1 • HSPA5 • IL1B • MFN2 • PTPN1 • TGFB1 • TNFA • XBP1

TRODUSQUEMINE: A PROMISING THERAPEUTIC MOLECULE FOR TDP-43 PROTEINOPATHIES (ADPD 2023) - "This study provides evidence that trodusquemine can prevent the pathological effects induced by TP D-43, putting forwards its potential as a new therapeutic candidate in TDP -43 proteinopathies."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Immunology • Proteinopathy • TARDBP

THE INVOLVMENT OF NMDA RECEPTORS IN THE PREVENTION OF ABETA OLIGOMERS TOXICITY BY TRODUSQUEMINE (ADPD 2023) - "All these data highlight a further mechanism of action by which trodusquemine prevent oligomer toxicity through the prevention of an excessive opening of NMDA receptors. In particular, in addition to inhibiting the binding of Ab42 ADDLs to cell membrane, trodusquemine also appears to prevent the ADDL -induced activation of NMDA receptors in case the oligomers are able to bind to the membrane. Furthermore, this study provides additional evidences that natural aminosterols can be pr omising molecules in the treatment of neurodegenerative diseases."

Alzheimer's Disease • CNS Disorders • CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor

The PTP1B selective inhibitor MSI-1436 mitigates Tunicamycin-induced ER stress in human hepatocarcinoma cell line through XBP1 splicing modulation. (PubMed, PLoS One) - "PTP1B inhibition using MSI-1436 could improve cellular apoptosis and metabolic integrity through the mitigation of ER and mitochondrial stress signalling pathways, and excessive ROS accumulation. This strategy may be useful for the treatment of metabolic disorders including IR, NAFLD and diabetes."

Journal • Preclinical • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Oncology • ATF6 • ERN1 • PTPN1 • XBP1

Multi-omics analyses of tumor-associated immune-infiltrating cells with the novel immune checkpoint protein tyrosine phosphatase 1B (PTP1B) in extracellular matrix of brain-lower-grade-glioma (LGG) and uveal-melanoma (UVM). (PubMed, Front Immunol) - "The homologous recombination deficiency (HRD) and loss of heterozygosity (LOH) were positive related to PTP1B expression in liver-hepatocellular-carcinoma (LIHC) and kidney-chromophobe (KICH), while the immunescore and immune infiltration displayed a significant positive correlation with PTP1B expression in LGG and UVM. Drug sensitivity tests showed that the PTP1B inhibitor MSI-1436 had a sensitivity effect suppressing tumor cell viability and suggested it enhanced the efficacy of PD-1 inhibitors in cancers."

IO biomarker • Journal • Acute Myelogenous Leukemia • Brain Cancer • Clear Cell Renal Cell Carcinoma • CNS Tumor • Eye Cancer • Gastrointestinal Cancer • Glioma • Hematological Malignancies • Hepatocellular Cancer • Immune Modulation • Inflammation • Leukemia • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • Uveal Melanoma • HRD • PTPN1

Reorganization of the outer layer of a model of the plasma membrane induced by a neuroprotective aminosterol. (PubMed, Colloids Surf B Biointerfaces) - "Removal of GM1 from the lipid L+S mixture resulted in an even greater TRO-mediated reduction of the size of the S domains suggesting that the presence of GM1 hinders the localization of TRO at the S domains boundaries. Taken together these observations suggest that Trodusquemine influences the organization of lipid rafts within the neuronal membrane in a dose-dependent manner whereas it evenly distributes in disordered expanded phases of the membrane model."

Journal • CNS Disorders

Status of research on natural protein tyrosine phosphatase 1B inhibitors as potential antidiabetic agents: Update. (PubMed, Biomed Pharmacother) - "However, the few PTP1B inhibitors that entered the clinic (Ertiprotafib, ISIS-113715, Trodusquemine, and JTT-551) were discontinued due to side effects or low selectivity. Molecules with broad chemical diversity extracted from natural products have been reported to be potent PTP1B inhibitors with few side effects. This article summarizes the recent PTP1B inhibitors extracted from natural products, clarifying the current research progress, and providing new options for designing new and effective PTP1B inhibitors."

Journal • Review • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • IR • LEP • PTPN1

Studying the trafficking of labeled trodusquemine and its application as nerve marker for light-sheet and expansion microscopy. (PubMed, FASEB J) - "We also found that TRO-A594 is able to strongly and selectively bind to myelinated fibers in fixed mouse brain slices, and that it is a marker compatible with tissue clearing and light-sheet fluorescence microscopy or expansion microscopy. In conclusion, this work contributes to further characterize the biology of aminosterols and provides a new tool for nerve labeling suitable for the most advanced microscopy techniques."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease

TRODUSQUEMINE PREVENTS TDP-43 INCLUSION FORMATION AND SUPPRESSES ITS TOXICITY IN VITRO AND IN VIVO (ADPD 2022) - "This study provides evidence that trodusquemine could be rationally optimized in drug discovery programs to target TDP-43 toxicity in ALS and other neurodegenerative diseases. The study was supported by Fondazione Cassa di Risparmio di Firenze (TROTHERALS to C.C.)."

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Targeted Protein Degradation • TARDBP