sobetirome (QRX 411) / Annovis Bio - LARVOL DELTA

Triiodothyronine activates THRβ to promote PGC1α expression alleviating PQ-induced pulmonary fibrosis. (PubMed, Ecotoxicol Environ Saf) - "T3 and sobetirome, a specific THRβ agonist significantly upregulated peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC1α) expression, and NH-3 (an antagonist of the thyroid hormone receptor), a THRβ-specific antagonist, significantly inhibited (P < 0.0001) the beneficial effects of T3 on the PQ-induced mitochondrial apoptotic pathway in an epithelial cell line, in vitro. T3 via the THRβ / PGC1α pathway protected against PQ induced pulmonary fibrosis, furnishing a scientific basis for further research on T3 and this pathway could offer a potential novel therapeutic strategy for treating PQ poisoning in humans."

Journal • Immunology • Pulmonary Disease • Respiratory Diseases

TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA. (PubMed, Nat Commun) - "Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice...Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis."

Journal • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CEBPA

Testing the sensitivity of the medaka Transgenic Eleuthero-embryonic THYroid-Specific assay (TETHYS) to different mechanisms of action. (PubMed, Aquat Toxicol) - "This assay is performed at eleuthero-embryonic life-stages with an exposure length of 72 h. In the present study, the following reference chemicals with known thyroid hormone system mechanism of action have been tested: methimazole, sodium perchlorate, sodium tetrafluoroborate, diclofenac, iopanoic acid, sobetirome, NH-3 and 1-850...To investigate the test specificity, we tested three chemicals presumed to be inert on the HPT axis: cefuroxime, abamectin and 17α-ethinylestradiol. All were found to be inactive in the TETHYS assay. This promising New Approach Methodology can serve as a foundation for the development of a new OECD TG in the frame of regulatory assessment of chemicals for thyroid activity."

Journal

Sobetirome rescues α-synuclein-mediated demyelination in an in vitro model of multiple system atrophy. (PubMed, Eur J Neurosci) - "Furthermore, myelination analysis using nanofibres confirmed that sobetirome increases both the length and number of myelinated segments per oligodendrocyte in primary murine α-syn overexpressing oligodendrocytes and their respective control. These results suggest that sobetirome may be a promising thyromimetic compound targeting an important neuropathological hallmark of MSA."

Journal • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Multiple System Atrophy • Parkinson's Disease • Solid Tumor

Thyromimetic actions of Sobetirome and its Amide Prodrug Sob-AM2 (ATA 2023) - No abstract available

TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice. (PubMed, Endocrinology) - "We used cell-based and in vivo assays to evaluate the effects of the TRβ agonist Sobetirome (GC-1) on a particularly aggressive and dedifferentiated cancer, anaplastic thyroid cancer (ATC). In xenograft assays, GC-1 alone inhibited tumor growth and was as effective as the kinase inhibitor, Sorafenib. These results indicate that selective activation of TRβ not only induces a tumor suppression program de novo but enhances the effectiveness of anti-cancer agents revealing potential novel combination therapies for ATC and other aggressive solid tumors."

Journal • Preclinical • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma

Development and validation for bioanalysis of VK2809, its active metabolite VK2809A and glutathione-conjugated metabolite MB06588 in rat liver using LC-MS/MS. (PubMed, J Pharm Biomed Anal) - "Subsequently, several factors were investigated such as the use of 60% acetonitrile for homogenization to stabilize the analytes, the addition of 20 mM glutathione for the derivation of VK2809B, and the protein precipitation with methanol containing Sobetirome as the internal standard (IS). This method is suitable for the bioanalysis of VK2809 and its metabolites and has been successfully applied to the study of intrahepatic exposure in rats. It is expected to be further practiced in drug design, optimization, and metabolism study in the following research."

Journal • Preclinical • Hepatology • Non-alcoholic Steatohepatitis

The Pulmonary Fibrosis Drug Connectome (ATS 2023) - "Interactive and dynamic visualizations as a function of selected cell types, genes, and compounds are presented to the user for exploration. During preliminary validation, signature queries of known antifibrotic drugs such as pirfenidone, nintedanib, saracatinib, and sobetirome gave predictions of lowered expression for a panel of genes known to be differentially expressed in several cell types in IPF, including GDF15, VIM, MMP7, COL1A1, CDKN1B, and CDKN1A. Our online drug repurposing platform represents the first use of scRNA-seq data to probe the effect of compounds in the CMap2020 database across combinatorial cell types. Given the flexibility of our signature generation, modification, and querying, we envision the IPF Connectome website as an accessible platform for real-time in silico compound identification for IPF."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Oncology • Pulmonary Disease • Respiratory Diseases • CDKN1A • CDKN1B • COL1A1 • COL4A1 • Collagen Type IV • GDF15 • MMP7

Thyroid Hormone Receptor β Agonist Sobetirome Attenuates Pulmonary Fibrosis Via Promoting Hyperplastic Alveolar Epithelial Type 2 Cells Differentiation Into Type 1 Cells (ATS 2023) - "RATIONALE Idiopathic pulmonary fibrosis (IPF), the most common form of the usual interstitial pneumonia, is a chronic, progressive, and lethal lung disease with unknown etiology. KLF2 conditional Knockout in AT2s accelerated the fibrosis in bleomycin model and impaired the therapeutic effect of GC-1. CONCLUSIONS These data fully proved that hyperplastic AT2s accumulation is the major reason of pulmonary fibrosis, and GC-1 effectively promoted the differentiation of these cells into AT1s, thereby repairing alveolar structure and attenuated pulmonary fibrosis with targets of KLF2."

Late-breaking abstract • Cardiovascular • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Interstitial Lung Disease • Osteoporosis • Pneumonia • Pulmonary Disease • Respiratory Diseases • Rheumatology • COL1A1 • PDPN • THRA

Promyelinating drugs promote functional recovery in an autism spectrum disorder mouse model of Pitt-Hopkins syndrome. (PubMed, Brain) - "In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt-Hopkins syndrome mouse model. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt-Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt-Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Psychiatry • Solid Tumor

Maternal administration of the CNS-selective sobetirome prodrug Sob-AM2 exerts thyromimetic effects in murine MCT8-deficient fetuses. (PubMed, Thyroid) - "Maternal administration of Sob-AM2 can cross the placental barrier and access the fetal tissues, including the brain, in the absence of MCT8, to exert thyromimetic actions by modulating the expression of T3-dependent genes. Therefore, Sob-AM2 has the potential to address the cerebral hypothyroidism characteristic of MCT8 deficiency from fetal stages and to prevent neurodevelopmental alterations in the MCT8-deficient fetal brain."

Journal • Preclinical • Endocrine Disorders

Identification of a Thyroid Hormone Binding Site in Hsp90 with Implications for Its Interaction with Thyroid Hormone Receptor Beta. (PubMed, ACS Omega) - "The binding of TRb to Hsp90 was prevented by T3 or by the thyroid mimetic sobetirome...Furthermore, T3 induced the release of bound TRb from Hsp90, which was shown by streptavidin-conjugated quantum dot (SAv-QD) masking assay. The data indicate that the T3 interaction with TRb and Hsp90 may be an amplifier of the cellular stress response by blocking Hsp90 activity."

Journal • HSP90AA1

Thyroid hormones and analogues promote the acute release of platelets from megakaryocytes: from blood donor biology to the production of platelets in vitro (ISTH 2022) - "Using metabolomics and proteomics screening methods, thyroid hormones have been identified as potent mediators of platelet production. Triiodothyronine (T3) as well as thyroid hormone analogues, GC-1 (Sobetirome), KB2115 (Eprotirome) and MGL-3196 showed a significant effect on platelet production, as well as proplatelet formation in vitro in both primary derived- and iPSC derived-megakaryocytes. These platelets that are produced under the influence of thyroid hormones are functionally active, showing degranulation (P-selectin exposure) and incorporation into thrombi."

Preclinical • Immune Modulation • Inflammation

Antifibrotic Effects of Sobetirome, a Thyroid Hormone Receptor Beta Agonist (ATS 2022) - "2018); here we demonstrate that sobetirome, a well-tolerated thyroid hormone receptor beta (THRB) agonist, exerts antifibrotic effects associated with improved mitochondrial function in lung cells.Methods.We used the bleomycin mouse model of pulmonary fibrosis to assess effects of intraperitoneal(300µg/kg every other day) or aerosol(300µg/kg daily) sobetirome administration, starting at day 8. Furthermore, it ameliorates mitochondrial function and affects apoptosis in two major effector cells in IPF, fibroblasts and ATII cells. Taken together, our results suggest that sobetirome should be considered and assessed as a potential future therapeutic compound for the treatment of IPF."

Fibrosis • Idiopathic Pulmonary Fibrosis • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • CASP3 • CASP7 • COL1A1 • COL3A1 • CTSK • FASLG • POSTN • PPARGC1A

[VIRTUAL] Biosynthesis and implementation of Thyroid Receptor beta (TRß) agonists (thyromimetics) for the treatment of pulmonary fibrosis (ERS 2021) - "Introduction: We have previously shown that administration of thyroid hormone and its analogue, sobetirome, attenuated bleomycin-induced lung fibrosis. Our study devised two novel thyromimetics with agonistic properties for ΤRβ and in-vivo therapeutic activity against bleomycin-induced lung injury. Thyromimetics may hold therapeutic promise for pulmonary fibrosis."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] The Thyroid Hormone Receptor Beta Agonist Sobetirome Exerts Beneficial Effects in Pulmonary Fibrosis (ATS 2021) - "To test our hypothesis, we used the bleomycin mouse model (intratracheal administration with therapeutic regimen starting at day 8, 300 µg/kg i.p. sobetirome every other day, sacrifice at day 21) of pulmonary fibrosis and performed the hydroxyproline assay to assess fibrosis. Taken together we could show that sobetirome exerts beneficial effects, both in vitro and in vivo, thus being a potential future therapeutic compound for the treatment of idiopathic pulmonary fibrosis. However, the exact mechanisms regulating this process still need to be explored, as well as biomarkers for target engagement and efficacy."

Cardiovascular • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases • CASP3 • CASP7

[VIRTUAL] RNA-Seq Reveals Antifibrotic Effects of Sobetirome in Human Lung Fibroblasts (ATS 2021) - "Sobetirome, a thyroid hormone receptor beta agonist, has recently been found to resolve lung fibrosis in bleomycin mouse model; we sought to investigate the effect of Sobetirome in human lung fibroblasts. This study demonstrates that Sobetirome may modify the profibrotic effects of TGF-β on lung fibroblasts. Future directions involve more research in the mechanisms of this effect."

Fibrosis • Idiopathic Pulmonary Fibrosis • Respiratory Diseases • KLF6 • POSTN • TGFB1

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis. (PubMed, Int J Mol Sci) - "In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability...By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases."

Journal • Amyloidosis • CNS Disorders

Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE. (PubMed, J Neuroimmunol) - "We investigated whether a thyroid receptor-beta selective thyromimetic, sobetirome (Sob), and its CNS-targeted prodrug, Sob-AM2, could prevent myelin and axonal degeneration in experimental autoimmune encephalomyelitis (EAE)...T3 and Sob also protected cultured oligodendrocytes against cell death. Thyromimetics thus might protect against oligodendrocyte death, demyelination and axonal degeneration as well as stimulate remyelination in multiple sclerosis."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor

Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH). (PubMed, PLoS One) - "In this study, we tested three THRβ-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THRβ and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism in vitro using human hepatic cells and in vivo using a rat model. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THRβ agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation."

Clinical • Journal • Addiction (Opioid and Alcohol) • Dyslipidemia • Hepatology • Non-alcoholic Steatohepatitis

Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders. (PubMed, Front Med (Lausanne)) - "In recent years, advances in molecular and structural biology have facilitated the design of new selective thyroid hormone mimetics that exhibit TR isoform-selective binding, and/or liver- and tissue-selective uptake, with Resmetirom (MGL-3196) and Hep-Direct prodrug VK2809 (MB07811) probably representing two of the most promising lipid lowering agents, currently under phase 2-3 clinical trials. Sob-AM2, a CNS- selective prodrug of Sobetirome has been shown to promote significant myelin repair in the brain and spinal cord of mouse demyelinating models and it is rapidly moving into clinical trials in humans. Taken together all these findings support the great potential of selective thyromimetics in targeting a large variety of human pathologies characterized by altered metabolism and/or cellular differentiation."

Journal • Review • CNS Disorders • Dyslipidemia • Hepatology • Metabolic Disorders • Multiple Sclerosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Solid Tumor

"Nope. This is AN19 (Sobetirome). Ibudilast is led by @gchupp & @maorsauler & Dr. Bucala @YaleRheumAller1 https://t.co/3xoI1zrZ9G" (@KaminskiMed)

Myelin repair stimulated by CNS-selective thyroid hormone action. (PubMed, JCI Insight) - "This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2...In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair."

Journal • CNS Disorders • Multiple Sclerosis • Solid Tumor

The Thyromimetic, GC-1, Alters Bile Acid Metabolism in a Mouse Model of Hepatic Cholestasis. (PubMed, Am J Pathol) - "Therefore, though GC-1 treatment induces a mild protection against biliary injury in the early stages of treatment, it comes at the expense of hepatocyte injury and is suboptimal due to lower expression of TRβ. Thus, thyromimetics may have limited therapeutic benefits in treating cholestatic liver disease."

Journal • Preclinical • Cholestasis • Hepatology

MCT8 Deficiency: The Road to Therapies for a Rare Disease. (PubMed, Front Neurosci) - "The use of thyroid hormone analogs such as TRIAC, DITPA, or sobetirome, that do not require MCT8 to cross cell membranes and whose controlled thyromimetic activity could potentially restore the normal function of the affected organs, are being explored to improve the cerebral availability of these analogs. Other strategies aiming to restore the transport of THs through MCT8 at the brain barriers and the cellular membranes include gene replacement therapy and the use of pharmacological chaperones. The design of an appropriate therapeutic strategy in combination with an early diagnosis (at prenatal stages), will be key aspects to improve the devastating alterations present in these patients."

Journal • Review • Endocrine Disorders • Rare Diseases