A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis in Glycogen Storage Disease Type Ia

Zhou, Jin; Waskowicz, Lauren R; Lim, Andrea; Liao, Xiao-Hui; Lian, Brian; Masamune, Hiroko; Refetoff, Samuel; Tran, Brian; Koeberl, Dwight D.; Yen, Paul M.

doi:10.1089/thy.2019.0007

Cited by 45 publications

(29 citation statements)

References 44 publications

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“…Another relevant point raised by these results is the potential usefulness of these analogues to reduce fatty liver and consequently NASH. Indeed, our previous results have shown that IS25 and its prodrug TG68 exert a strong effect on lipolysis in human hepatoma (HepG2) cells, 23,24 in agreement with the effect of GC‐1 and other thyromimetics on NAFLD/NASH 16‐18,22 …”

Section: Discussionsupporting

confidence: 74%

“…Indeed, GC‐1 has been shown to prevent the development and progression of rat fatty liver by increasing mitochondrial and peroxisomal fatty acid β‐oxidation and reduced levels of inflammatory markers 16 . Similarly, MB07344 and its prodrug MB07811 showed anti‐steatotic activity in different animal models 17,18 . Due to their beneficial effects, two of the aforementioned designed analogues, GC‐1 and KB2115, commercially known as sobetirome and eprotirome, respectively, entered human clinical trials for dyslipidaemia, displaying encouraging results in the absence of harmful effects typically associated with thyroid hormones (THs) high levels (for reviews, see 19,20).…”

Section: Introductionmentioning

confidence: 99%

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Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

et al. 2020

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Objectives Although the hepatomitogenic activity of triiodothyronine (T3) is well established, the wide range of harmful effects exerted by this hormone precludes its use in liver regenerative therapy. Selective agonists of the beta isoform of thyroid hormone receptor (TRβ) do not exhibit T3‐induced cardiotoxicity and show a good safety profile in patients with NASH. The aim of this study was to investigate whether two novel TRβ agonists, the prodrug TG68 and the active compound IS25 could stimulate hepatocyte proliferation without T3/TRα‐dependent side effects. Methods Rats were treated with three different doses (12.5, 25 and 50 μg/100 g body weight) for one week. Hepatocyte proliferation, liver injury and serum biochemical parameters were measured by immunohistochemistry, qRT‐PCR and Western blot. Results Both drugs increased hepatocyte proliferation as assessed by bromodeoxyuridine incorporation (from 14% to 28% vs 5% of controls) and mitotic activity. Enhanced proliferation occurred in the absence of significant signs of liver injury as shown by lack of increased serum transaminase levels or of apoptosis. No cardiac or renal hypertrophy typically associated with treatment with T3 was observed. Importantly, no proliferation of pancreatic acinar cells, such as that seen after administration of T3 or the TRβ agonist GC1 was detected following either TG68 or IS25, demonstrating the hepato‐specificity of these novel TRβ agonists. Conclusions The present study shows that TG68 and IS25 induce massive hepatocyte proliferation without overt toxicity. Hence, these agents may have a significant clinical application for regenerative therapies in liver transplantation or other surgical settings.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

et al. 2020

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“…Again, the magnitude of MGL-3196induced transcription was lower compared to the effect of T3, and the increase in liver Dio1 expression between 1.5 and 5 mg/kg of MGL-3196 was only 1.3-fold ( Fig 4C). Furthermore, VK2809 treatment in mice has been shown to increase the expression of CPT1A [50], a gene that we have confirmed as THR target in both Huh-7 cells and in rat liver (Fig 2D and 4A). Taken together, our in vitro and in vivo results comparing clinically relevant molecules provide a roadmap for the rapid screening of potent and selective liver targeting…”

Section: Discussionmentioning

confidence: 57%

Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH)

Luong¹,

Stevens²,

Jekle³

et al. 2020

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Thyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THRβ agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. 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. Treatment with GC-1 upregulated the transcription of CPT1A in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely, ANGPTL4 and DIO1. In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver Dio1 and Me1 RNA expression. 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.

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“…Recently, a new strategy to overcome the detrimental effects related to TR activation in extrahepatic tissues has been the development of liver targeting “TR agonist prodrugs.” VK2809 is the most promising of the prodrug candidates and was originally developed by Metabasis Therapeutics, Inc., under the name of MB07811 (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl) phenoxy)methyl]-2-oxido-[1–3]-dioxaphosphonane ( 24 , 72 ). Notably, from a structural point of view, this new generation of Hep-Direct prodrugs are small aryl-substituted cyclic prodrugs ( Figure 3 ) that are able to generate the active drug after oxidation of the benzylic methine proton produced by the cytochrome P450 (CYP) isoenzyme CYP3A.…”

Section: Sobetirome and Novel Diphenylmethane Structure Based Thyromimentioning

confidence: 99%

“…These molecules showed great promise of becoming drugs for the treatment of lipid metabolism disorders, but ultimately failed to reach the therapeutic market because of the onset of unwanted side-effects ( 23 ). Noteworthy, in recent years there has been a resurgence of interest in developing TRβ selective thyromimetics, and in particular “tissue-selective prodrugs” able to release the desired active compound at the site of action ( 24 ). The aim of the present review is to provide an update regarding the most significant steps toward the obtainment of clinically useful thyromimetics, providing further details on a subject that has already been widely discussed in recent reviews ( 25 , 26 ).…”

Section: Introductionmentioning

confidence: 99%

Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders

et al. 2020

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Thyroid hormones (THs) elicit significant effects on numerous physiological processes, such as growth, development, and metabolism. A lack of thyroid hormones is not compatible with normal health. Most THs effects are mediated by two different thyroid hormone receptor (TR) isoforms, namely TRα and TRβ, with the TRβ isoform known to be responsible for the main beneficial effects of TH on liver. In brain, despite the crucial role of TRα isoform in neuronal development, TRβ has been proposed to play a role in the remyelination processes. Consequently, over the past two decades, much effort has been applied in developing thyroid hormone analogs capable of uncoupling beneficial actions on liver (triglyceride and cholesterol lowering) and central nervous system (CNS) (oligodendrocyte proliferation) from deleterious effects on the heart, muscle and bone. Sobetirome (GC-1) and subsequently Eprotirome (KB2115) were the first examples of TRβ selective thyromimetics, with Sobetirome differing from the structure of thyronines because of the absence of halogens, biaryl ether oxygen, and amino-acidic side chain. Even though both thyromimetics showed encouraging actions against hypercholesterolemia, non-alcoholic steatohepatitis (NASH) and in the stimulation of hepatocytes proliferation, they were stopped after Phase 1 and Phase 2–3 clinical trials, respectively. 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. More recently the application of a comprehensive panel of ADME-Toxicity assays enabled the selection of novel thyromimetic IS25 and its prodrug TG68, as very powerful lipid lowering agents both in vitro and in vivo . In addition to dyslipidemia and other liver pathologies, THs analogs could also be of value for the treatment of neurodegenerative diseases, such as multiple sclerosis (MS). 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.

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A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis in Glycogen Storage Disease Type Ia

Cited by 45 publications

References 44 publications

Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH)

Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders

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