Scientific Background
Lung Cancer
Lung cancer is the most common form of cancer in the world (12.3% of all cancers), with an estimated 2.2 million individuals diagnosed worldwide with lung cancer in 2020. There are clearly unmet medical needs in this area and specifically, in new therapeutic strategies allowing the improvement of the survival rate of NSCLC patients.
The MET kinase exon 14 mutation has been identified in ~3% of NSCLC patients whilst patients with MET amplification also represents around 2% of NSCLC.
Regulatory authorities have already approved MET kinase inhibitors as therapies against NSCLC carrying the MET kinase exon 14 mutation.
MET Inhibitors
Mesenchymal epithelial transition (MET) tyrosine kinase inhibitors are drugs used for treating lung cancer. The MET tyrosine kinase is a receptor present on the surface of various cells. These receptors have a ligand called hepatocyte growth factor (HGF). The binding of HGF to MET receptors leads to cell formation and wound healing in normal cells. However, mutations of MET can lead to the overactivity of cells, leading to tumour development.
MET tyrosine kinase inhibitors are used to treat non-small- cell lung cancer (NSCLC) in adults. They have recently been approved for patients with NSCLC harbouring the MET exon 14 skipping mutation, the efficacy rates observed are of the order of 50% (Objective Response rate), yet they all suffer from the same issues: poor tolerability leading to frequent dose reductions and interruptions that result in suboptimal target inhibition and therapy resistance. All agents in this class report similar issues and hence require high maximum tolerated clinical doses to achieve efficacious exposures. A consequence of these high daily doses is the formation of high levels of inactive metabolite(s) with low solubility and toxic effects.
Deuteration
A deuterated drug is a small molecule in which one or more of the hydrogen atoms are replaced by deuterium.
As deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be made to a molecule
“Deuterium-carbon”bonds are 6 to 10 times more stable than the corresponding carbon-hydrogen bonds
- More difficult to break
- Slows the rate of bond cleavage: Kinetic Deuterium Isotope effect (KDIE)
- KDIE could impact the biological fate of many drugs that are metabolised by pathways involving carbon-hydrogen bond scission
