mitoglitazone (MSDC-0160) / Metabolic Solutions - LARVOL DELTA

Proanthocyanidin and mitoglitazone suppress lipogenesis by targeting ferroptosis in metabolic dysfunction-associated steatohepatitis. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "On the other hand, Mito, Pro, and their combination significantly improved ferroptotic biomarkers (GSH, GPX4, sTFR1, and total iron and ACSL-4 gene expression), glucose homeostasis, lipid profile, liver enzymes, and histology compared to MASH group. Combining the insulin-sensitizing properties with targeting of ferroptosis, by the co-treatment with mitoglitazone (MSDC-0160) and proanthocyanidin, could be beneficial in inhibition of lipogenesis with retardation of MASH development in mice."

Journal • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • ACSL4 • GPX4

Glyceraldehyde-3-Phosphate Dehydrogenase/1,3-Bisphosphoglycerate-NADH as Key Determinants in Controlling Human Retinal Endothelial Cellular Functions: Insights from Glycolytic Screening. (PubMed, J Biol Chem) - "Pharmacological inhibitors targeting lower glycolytic components were tested: heptelidic acid for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), NG-52 for phosphoglycerate kinase (PGK), shikonin for pyruvate kinase M (PKM), galloflavin for lactate dehydrogenase (LDH), AZD3965 for lactate transporter (MCT-1), and MSDC-0160 for the mitochondrial pyruvate carrier (MPC)...GAPDH and its downstream products (1,3-BPG and NADH) are shown to play a pivotal role in maintaining barrier integrity and promoting HREC adhesion and spreading. These findings guide the development of targeted interventions that modulate HREC bioenergetics to treat endothelial dysfunction in various retinal disorders, while minimizing potential adverse effects on healthy endothelial cells."

Journal • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • GAPDH • PKM

Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma. (PubMed, Neuro Oncol) - "Our findings demonstrate the critical role of the MPC in mediating GBM aggressiveness and molecular evolution following standard TMZ-RT treatment, illuminating a therapeutically-relevant metabolic vulnerability to potentially improve survival outcomes for GBM patients."

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

Structure-based multitargeted docking screening, pharmacokinetics, DFT, and dynamics simulation studies reveal mitoglitazone as a potent inhibitor of cellular survival and stress response proteins of lung cancer. (PubMed, Med Oncol) - "Further, the results were validated with SPC water model-based MD simulation for 100ns in neutralised condition, showing the cumulative deviation and fluctuation < 2Å with many intermolecular interactions. The whole analysis has suggested that Mitoglitazone can be used as a multitargeted inhibitor against lung cancer-however, experimental studies are needed before human use."

Journal • PK/PD data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Insulin sensitizers in 2023: lessons learned and new avenues for investigation. (PubMed, Expert Opin Investig Drugs) - "Pioglitazone remains the best in class with beneficial pleiotropic pharmacology, although use is limited by tolerability issues...Greater understanding of the mechanism of action of insulin sensitizing drugs can expand the rationale for the fields of treatment and potential for treatment combinations. This understanding can facilitate the registration and broader use of agents with that impact the pathophysiology that underlies chronic metabolic diseases as well as host responses to environmental insults including pathogens, insulin sensitizer, MPC, mitochondrial target, metabolic reprogramming, chronic and infectious disease."

Journal • Review • Cardiovascular • Diabetes • Infectious Disease • Metabolic Disorders • Type 2 Diabetes Mellitus • PPARG

Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells. (PubMed, Nat Commun) - "Finally, we demonstrate that MSDC-0160, a clinical orally-available MPC1/2 inhibitor, inhibits pyruvate anaplerosis and targets imatinib-resistant CML LSCs in robust pre-clinical CML models. Collectively these results highlight pyruvate anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient-derived samples."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1

Glycolytic System in Axons Supplement Decreased ATP Levels after Axotomy of the Peripheral Nerve. (PubMed, eNeuro) - "Glycolytic inhibitors, 2-deoxyglucose (2-DG) and MCT inhibitors, a-cyano-4-hydroxycinnamic acid (4-CIN) decreased ATP and enhanced WD progression, whereas mitochondrial pyruvate carrier (MPC) inhibitors (MSDC-0160) did not change. Axons also activate the glycolysis system to obtain ATP, and inactivate TCA cycle due to mitochondrial degeneration. The glycolysis with MCT-induced monocarboxylate transport contributes to the ATP production in degenerative axons."

Journal • CNS Disorders

Mitoglitazone ameliorates renal ischemia/reperfusion injury by inhibiting ferroptosis via targeting mitoNEET. (PubMed, Toxicol Appl Pharmacol) - "In this study, compared with the antidiabetic TZD pioglitazone (PGZ), we found its derivative mitoglitazone (MGZ) exerted significantly inhibitory effects on erastin-induced ferroptosis by suppressing mitochondrial membrane potential hyperpolarization and lipid ROS production in HEK293 cells. Mechanistically, molecular docking and surface plasmon resonance experiments demonstrated that MGZ exhibited a high binding affinity with the mitochondrial outer membrane protein mitoNEET. Collectively, our findings indicated the renal protective effect of MGZ was closely linked to regulating the mitoNEET-mediated ferroptosis pathway, thus offering potential therapeutic strategies for ameliorating I/R injuries."

Journal • Cardiovascular • Immunology • Inflammation • Metabolic Disorders • Reperfusion Injury • Transplant Rejection • Transplantation • GPX4

Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming. (PubMed, Immunology) - "We found that inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC-0160 or pioglitazone, increased NLRP3 inflammasome activation and IL-1β secretion in macrophages. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3-related autoinflammatory diseases."

Journal • Diabetes • Gout • Inflammation • Inflammatory Arthritis • Metabolic Disorders • Rheumatology • IL1B • NLRP3

Re-routing Metabolism by the Mitochondrial Pyruvate Carrier Inhibitor MSDC-0160 Attenuates Neurodegeneration in a Rat Model of Parkinson's Disease. (PubMed, Mol Neurobiol) - "Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation, and glutamate oxidation to satisfy energy needs and maintain energy homeostasis. MSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism."

Journal • Preclinical • CNS Disorders • Immunology • Inflammation • Metabolic Disorders • Movement Disorders • Parkinson's Disease

Surprising discoveries while using deuterium to stabilize enantiomers for chiral switching (ACS-Sp 2022) - "Below are highlights of the effects observed with several racemic compounds including pioglitazone, mitoglitazone, inolitazone, prasugrel, donepezil, lenalidomide, avadomide, iberdomide, and bupropion.Stabilization with deuterium may vary:- by compound even within the same compound class (e.g., thiazolidinediones); and- as a function of stereochemistry (sometimes there is no stabilization for one of the enantiomers).To date, the effects observed when deuterium is used to stabilize enantiomers include:1...Reduced rates of degradation – in addition to reduced enantiomerization (e.g., degradation of thalidomide analogs varies from none to 4x).3...Stereoselective formation of one protonated enantiomer versus the other due to different reaction kinetics (e.g. d-R forms predominately h-R vs h-S).5. Sometimes limited predictive value for in vivo effects of in vitro D/H exchange and enantiomerization studies."

Construction and Comprehensive Analysis of Dysregulated Long Noncoding RNA-Associated Competing Endogenous RNA Network in Moyamoya Disease. (PubMed, Comput Math Methods Med) - "Finally, two potential small molecule drugs, CAY-10415 and indirubin, were identified by CMap as candidate drugs for treating MMD. The present study used bioinformatics analysis of candidate RNAs to identify a series of clearly altered miRNAs, lncRNAs, and mRNAs involved in MMD. Furthermore, a ceRNA lncRNA-miRNA-mRNA regulatory network was constructed, which provides insights into the novel molecular pathogenesis of MMD, thus giving promising clues for clinical therapy."

Journal • Immunology

Metabolic Solutions Development Company presents phase 2a clinical trial results at the 14th International Conference on Alzheimer's Drug Discovery (PRNewswire) - P2a, N=40; NCT01374438; Sponsor: Metabolic Solutions Development Company; "Metabolic Solutions Development Company, LLC (MSDC) has announced that Jerry Colca, PhD, co-founder and chief scientific officer of MSDC, will present results of a phase 2a study on September 9 at the 14th International Conference on Alzheimer's Drug Discovery..."

Anticipated P2 data • Alzheimer's Disease

Metabolic Solutions to present MSDC-0160 clinical candidate data at EASD conference (News-Medical) - Metabolic Solutions to present MSDC-0160 clinical candidate data at EASD conference on Sep 23 ’10;

Anticipated presentation • Diabetes

Metabolic Solutions Development Company presents new brown fat research at the European Association for the study of diabetes (PRNewswire) - The brown-like adipose cells express UCP1 message & protein in process that includes increased mitochondrial biogenesis; These effects were not attenuated by the potent PPARy antagonists, T0070907 & GW9662, confirming PPAR-independent pharmacology of MSDC compound

Preclinical-animal • Diabetes

Insulin sensitizers regulate pyruvate oxidation through a mitochondrial target (mTOT) (ADA 2012) - Publication-only abstracts; MSDC-0160 at 10μM reduces uncoupler-stimulated respiration rates by roughly 50% in cells oxidizing pyruvate, but has no effect on the rate of oxidation of glutamate, succinate, or palmitoyl carnitine

Review • Diabetes

Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. (PubMed, Nat Metab) - "In turn, we apply a clinically viable small molecule targeting the MPC, MSDC0160, to pre-clinical PCa models and find that MPC inhibition suppresses tumor growth in hormone-responsive and castrate-resistant conditions. Collectively, our findings characterize the MPC as a tractable therapeutic target in AR-driven prostate tumors."

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