MICA: Novel inhibitors of Transglutaminase 2 (TG2), a new therapy to halt the progression of diabetic cardiomyopathy

Lead Research Organisation: Aston University
Department Name: College of Health and Life Sciences

Abstract

Heart failure and heart attacks are more frequent in people suffering from Type 2 diabetes and have exceptionally poor outcomes despite current best clinical management. This is because the heart contains increased amounts of fibrous material (fibrosis) which has accumulated in the heart muscle affecting its ability to pump blood around the body, a condition known as diabetic cardiomyopathy.
The proposed project is aimed at overcoming this problem by inhibiting the activity of the multifunctional enzyme protein called Transglutaminase 2 (TG2). TG2 contributes to the development of fibrosis by crosslinking certain proteins together "like a glue" which facilitates the increased deposition of the fibrous material in the heart. This "protein mesh" is now highly resistant to remodelling and normal tissue repair is compromised which can lead to heart failure.

Preliminary work at Aston has resulted in powerful chemicals that inhibit TG2 and could be developed into drugs that prevent the crosslinking glue-action thus, enabling the heart to remodel the damaged areas and form healthy tissue. We aim to build on this early work by seeking further improvements in the drug properties of our early inhibitor compounds of TG2 .

Our ultimate goal is to generate TG2 inhibiting compounds that are ready to test in animals (to show that they work and that they do not cause dangerous side effects) and also to progress these inhibitors towards a candidate drug that can be administered to human patients to prevent the progression of fibrosis and reduce the incidence of heart failure and heart attacks in patients suffering from diabetic cardiomyopathy.

Technical Summary

Cardiovascular disease remains the foremost cause of death across the industrialised world. The risk of developing heart failure is significantly increased in the presence of type 2 diabetes (T2D) which affects over 300 million people worldwide. T2D sufferers also have a higher risk of and worse outcome following myocardial infarction with metabolic and morphologic changes in the myocardium leading to fibrosis as a common final pathway.The term 'Diabetic cardiomyopathy' (DCM) summarises these complex changes. The mortality risk increases tenfold, and five-year survival is 12.5% in T2D patients with DCM. Targeted therapies of DCM are urgently needed.
This project aims to halt the development of myocardial fibrosis in DCM by targeting the protein crosslinking enzyme Transglutaminase 2 (TG2). Aided by structure based drug design (SBDD) Aston has developed a series of highly potent and selective TG2 inhibitors. Our preliminary studies demonstrated the efficacy of these compounds in both cells and two animal models of cardiac fibrosis.
Our objective is to improve the Pharmacokinetic (PK) characteristics of our lead series of compounds, while maintaining potency and selectivity.
We will use a combination of synthetic chemistry,SBDD and in vitro screening to generate improved compounds that combine appropriate stability and aqueous solubility, TG2 activity, cellular efficacy and in vivo target engagement. Compounds will be tested in vitro using enzyme and cell screens and by DMPK and toxicity assays and in vivo for PK, Pharmacodynamics (PD) and toxicity. Lead compounds will be initially screened for efficacy in a mouse model of chronic fibrosis, i.e. the transverse aortic constriction model. DMPK characterisation will be performed throughout with more intensive studies expected in the final development stage. In the later stages of year 2, lead compounds will be tested for efficacy in a mouse DCM model and also tested for in vivo toxicity.

Planned Impact

Patient Impact
Our initial disease indication is cardiac fibrosis arising from diabetic cardiomyopathy. Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes leading to the excessive accumulation of collagen and dysfunctional remodelling of the myocardium.
Development of a treatment to halt and reverse the progression of cardiac fibrosis in people suffering from diabetic cardiomyopathy has the potential to decrease their increased susceptibility to heart failure and heart attacks.

Direct benefits to the researchers involved.
This project will also provide great training opportunities for the PDRAs involved in the project. PDRAs will benefit directly from their involvement in this interdisciplinary project and in particular with their interaction with the participating institutions (Aston and Leeds). This will not only lead to the enhancement of the research base of the local environment but also that of the UK.

Impact on the broader research community
The data generated will increase our understanding of the role that the multifunctional Transglutaminase 2 (TG2) plays in cardiac fibrosis using the TG2 selective inhibitors developed in this project. Importantly it will prove our concept for the importance of TG2 as a potential therapeutic target in cardiac fibrosis and potentially in other fibrotic conditions. This work will also have an influence of medicinal chemists who are also working on new candidate molecules that inhibit TG2.

Dissemination of Data
First and foremost the impact of our work will be realised by publishing our results and conclusions to a large scientific audience in research articles, a review and presentations at international and local congresses. The findings of this project will also be of interest to the general public due to its potential importance in the treatment of diabetic cardiomyopathy and other fibrotic diseases.

Impact on clinicians and Health Service
The development of an effective inhibitor that prevents the progression of diabetic cardiomyopathy resulting in fibrosis and remodelling of the myocardium will have a large impact on the treatment of this disease and will also have a large impact on health care costs since it is likely to reduce the incidence of heart failure and heart attacks resulting from this condition.It will also influence Clinicians involved in the treatment of cardiac fibrosis and diabetes and stimulate further thinking into the improvement of present drugs.

Publications

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