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

Ganaxolone, an approved therapy for CDKL5-Deficiency Disorder, is an inhibitor of PTP1B. (PubMed, J Biol Chem) - "We observed that ganaxalone was able to inhibit PTP1B activity both in an in vitro assay of enzyme activity and in different cell models, with similar potency to known inhibitors of PTP1B, including MSI-1436, which has a similar chemical structure. In these cells, inhibition of PTP1B not only brought BDNF signaling to levels similar to those of wild-type cells, but also restored cellular morphology. Our results suggest that, like in Rett syndrome, targeting PTP1B may be a beneficial therapeutic strategy for CDD."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Movement Disorders • CDKL5 • PTPN1

Myeloid Cell Protein Tyrosine Phosphatase 1B Drives Retinal Neurodegeneration in Diabetic Mice. (PubMed, Diabetes) - "PTP1B mediates superoxide production, decreases mitochondrial membrane potential, and, in female mice, increases macrophage cell death in chronic conditions associated with abnormally high glucose levels. Protective effects of PTP1B deletion on diabetic retinopathy were also observed in mice treated with the small molecular PTP1B inhibitor MSI-1436; both retinal neurodegeneration and local glial cell activation were decreased."

Journal • Preclinical • CNS Disorders • Diabetes • Diabetic Retinopathy • Inflammation • Metabolic Disorders • Ocular Inflammation • Retinal Disorders • PTPN1

Evaluation of intrinsic Young's modulus and stiffening effect of trodusquemine in phase-separated supported lipid bilayers. (PubMed, J Colloid Interface Sci) - "The highest increase was measured at the lowest concentration tested of 1 μM, supporting the relevance and therapeutic potential of this class of molecules at physiologically achievable doses. Overall, this study provides a methodological framework for investigating the mechanical properties of supported thin films endowed of a complex texture."

Journal • CNS Disorders

PTP1B Inhibitors for Type 2 Diabetes: From Natural Products, Synthetic Inhibitors, and Multi-Target Drug Design Strategies to Clinical Translation. (PubMed, Curr Drug Targets) - "The development of PTP1B inhibitors requires integrated approaches that include allosteric modulation, tissue-specific delivery, and patient stratification to achieve successful clinical translation across multiple disease indications."

Journal • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Oncology • Targeted Protein Degradation • Type 2 Diabetes Mellitus • PTPN1 • PTPN2

MODULATION OF TDP-43 PATHOLOGY BY THE AMINOSTEROL TRODUSQUEMINE (ADPD 2026) - "These findings demonstrate that TRO counteracts TDP-43 pathology via a dual mechanism, modulation of both phase separation dynamics and PTP-1B pathway, thus highlighting its potential as a therapeutic candidate for TDP-43–related neurodegenerative proteinopathies. This study was supported by NextGenerationEU, PRIN 2022 PNRR, CUP «B53D23028100001», project P20225ZPYH to R.C.."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Proteinopathy • PTPN1 • TARDBP

Multi-target mechanisms of glabrone in ulcerative colitis: Synergistic restoration of mucosal barrier and inhibition of inflammation through SRC/HSP90 Co-modulation. (PubMed, Biomed Pharmacother) - "Glabrone ameliorates UC through coordinated modulation of SRC/HSP90, which synergistically promotes mucosal barrier restoration and suppresses inflammatory responses. These results provide theoretical basis for developing Glabrone as a candidate multi-target therapeutic agent for UC."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • CDC37 • CLDN1 • ER • HSP90AA1 • IL1B • IL6 • OCLN • TJP1 • TNFA

Ganaxolone, an approved therapy for CDKL5-Deficiency Disorder, is an inhibitor of PTP1B. (PubMed, bioRxiv) - "We observed that ganaxalone was able to inhibit PTP1B activity both in an in vitro assay of enzyme activity and in different cell models, in a comparable way to known inhibitors of PTP1B, including MSI-1436, which has a similar chemical structure. Finally, loss of CDKL5 function resulted in increased levels of PTP1B. Our results suggest that, like in Rett syndrome, targeting PTP1B may be a beneficial therapeutic strategy for CDD."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Movement Disorders • CDKL5 • PTPN1

Protein Tyrosine Phosphatase 1B Inhibition Rescues From Metabolic Dysfunction-Induced Cardiomyopathy And HFpEF (AHA 2025) - "Our findings indicate PTP1B inhibition mitigates metabolic dysfunction and associated cardiac remodeling, suggesting that Trodusquemine may be a promising therapeutic candidate for treatment of HFpEF."

Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Fibrosis • Genetic Disorders • Heart Failure • Immunology • Metabolic Disorders • Obesity • PTPN1

Inhibition of PTP1B Through NADH Dehydrogenase Activity Reduces Acute Pancreatic Acinar Cell Pyroptosis by Inhibiting the ROS/TXNIP/NLRP3 Pathway. (PubMed, Dig Dis Sci) - "Targeting PTP1B mitigates CAE-induced pyroptosis in pancreatic acinar cells by restoring NADH dehydrogenase activity and suppressing ROS/TXNIP/NLRP3 inflammasome activation."

Journal • Inflammation • Pancreatitis • CASP1 • CASP4 • CASP5 • IL18 • IL1B • NLRP3 • PTPN1 • TXNIP

High Efficiency Labeling of nerve Fibers in cleared tissue for light-sheet microscopy. (PubMed, J Neurosci Methods) - "Our data support the potential use of HELF coupled to LSFM as a practical tool for the evaluation of novel therapeutics for remyelination in preclinical models of CNS diseases."

Journal • CNS Disorders • Multiple Sclerosis

Guardians of the sea: molecular and biochemical adaptations in sharks and whales for atherosclerosis resistance and their potential in human cardioprotection. (PubMed, Diabetol Metab Syndr) - "Sharks demonstrate potent anti-angiogenic peptides and aminosterols (e.g., squalamine, trodusquemine) that modulate key pathways like PTP1B inhibition, thus reducing inflammation and endothelial dysfunction...Future therapeutic strategies must resolve challenges in ethical sourcing, bioavailability, and scalability. CLINICAL TRIAL NUMBER: Not applicable."

Journal • Review • Atherosclerosis • Cardiovascular • Inflammation • PTPN1

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