Cantoni Therapeutics is a biopharmaceutical spinout company
from the University of Leiden (NL)
About
Cantoni Therapeutics
Cantoni Therapeutics is a biopharmaceutical spinout company from the University of Leiden (NL) developing best-in-class inhibitors targeting a single enzyme with a dual therapeutic effect to benefit patients with metabolic syndrome.
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About
Metabolic syndrome
Metabolic syndrome is caused by an unhealthy lifestyle, defined by the WHO as a combination of behavioural factors including the consumption of a diet with inadequate fruit and vegetables, tobacco smoking, physical inactivity, a sedentary lifestyle, and alcohol consumption. Key aspects of metabolic syndrome include obesity and type II diabetes, which are generally connected to a wide variety of complications, including heart disease, kidney disease, fatty liver disease, glaucoma, neuropathy and diabetic foot disease.
Metabolic syndrome comprises of a combination of obesity, high blood pressure, type II diabetes, high triglycerides and low HDL and high LDL cholesterol.
Visceral obesity
Hypertension
Insulin Resistance
High Triglycerides
Low HDL-Cholesterol
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global widespread prevalence
Type 2 diabetes has global widespread prevalence with steep growth perspectives both in number of patients as well as in market size. Worldwide the number of patients with type 2 diabetes is expected to increase from 537 million today to 643 million in 2030. The disease is responsible for 6.7 million deaths annually. The economic impact of diabetes is huge and growing continuously from an estimated direct cost of 232 billion USD in 2007 to 966 billion in 2021.
Contact usEstimated increase in number of type II diabetes patients from 2021 to 2045
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Obesity
Current treatment options start with dietary intervention and exercise regiments to change and improve the patients’ lifestyle. Subsequent treatment options focus on reaching glycaemic control using one or more antidiabetic medications. However, these drugs do not affect the root causes of type 2 diabetes, like excess body weight, hindering to achieve control of blood glucose metabolism. This results in about 40% of diabetic patients not being able to reach glycaemic control.
Looking at obesity, the prevalence worldwide has increased exponentially over the last few decades as illustrated in the clip.
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NNMT
Nicotinamide N-methyltransferase (NNMT) is a cytosolic small molecule methyltransferase enzyme responsible for the conversion of nicotinamide (NA, vitamin B3) to 1-methylnicotinamide (MNA). NNMT utilizes the cofactor S-adenosyl-l-methionine (SAM) as a methyl donor, which is converted to S-adenosyl-l-homocysteine (SAH) upon methylation of nicotinamide (figure 1.)
Under normal physiological conditions, NNMT is primarily expressed in the liver where it plays a key role in the detoxification of xenobiotics. Recently, however, NNMT overexpression has also been found in other tissues, such as adipocytes and a number of human cancers. Elevated NNMT activity is correlated with obesity, insulin resistance and blood glucose levels as well as tumor aggressiveness and is proposed to promote cancer migration, invasion, and proliferation through epigenetic changes.
Figure 1. Graphical representation of the methylation of nicotinamide (NA) catalysed by Nicotinamide N-methyltransferase (NNMT) utilizing S-adenosyl-l-methionine (SAM) as a methyl donor. The products of the enzymatic reaction are S-adenosyl-l-homocysteine (SAH) and 1-methylnicotinamide (MNA).
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Mechanism of action
NNMT acts on both the NAD+ cycle and the methionine cycle as illustrated in figure 2. After methylation of nicotinamide, the MNA formed is excreted, reducing available nicotinamide to participate in the NAD+ cycle. At the same time, the available SAM is converted to SAH leading to a decrease in the SAM/SAH balance also known as the methylation potential of cells. The change in the SAM/SAH balance directly affects other SAM-dependent methyltransferase enzymes involved in gene regulation and transcription.
Figure 2. Schematic representation of the mechanism of action of NNMT with the red arrows indicating the effect of NNMT inhibition (NNMTi)
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NNMT Inhibition
Cantoni Therapeutics has developed a portfolio of best-in-class inhibitors of NNMT, acting as bisubstrate inhibitors. Our inhibitors not only are the most potent NNMT inhibitors described to date, but differentiate from other NNMT inhibitors through binding in both the SAM and NA binding pockets in the active site of NNMT. Other inhibitors are shown to be competitive with NA only and are dependent on the concentration of SAM for their binding. Lower concentrations of SAM and higher concentrations of NA will decrease the inhibitory activity of these compounds. Considering that NNMT significantly reduces the available SAM and distorts the SAM/SAH balance, this decreases the NA-competitive inhibitors’ ability to bind to NNMT. In addition, increased intake of NA, which is linked to increased levels of NNMT, will also negatively affect the NA-competitive inhibitors’ mechanism of action through direct competition. Conversely, our bisubstrate inhibitors are competitive with both SAM and NA, but not dependent on either of the two substrates of NNMT and are less affected by the local concentrations of SAM and NA because of their tight binding kinetics. The difference in mechanism of action is illustrated in figure 3.
Figure 3. Mechanism of action of NA-competitive and SAM-dependent inhibitors compared to that of the bisubstrate inhibitors of NNMT