Report on Novel mTOR Inhibitor as a Potential Treatment

Two publications from the lab of Dr. Wolfgang Löscher, an Epilepsy Foundation grant awardee, present findings about the discovery of a novel mTOR inhibitor called PQR620 and its potential role in treating chronic epilepsy. 

Background

• Mechanistic target of rapamycin (abbreviated mTOR) is an enzyme that is over-activated in many kinds of cancers and certain neurological disorders.
• mTORs such as everolimus are used in clinical practice. However, they typically are poorly tolerated and do not enter the brain well enough to be a good treatment option.
• Previous studies have identified a novel mTOR inhibitor called PQR620 and suggested its potential as a treatment option. 

Purpose

In two studies, Dr. Löscher and his team sought to

1. Characterize PQR620 in various cancer lines and in a mouse model of Tuberous Sclerosis Complex (TSC). An additional aim was to see how the drug PQR620 distributes in brain and plasma. 
2. Examine whether PQR620 crosses the blood brain barrier and look at how changed the seizure threshold in experimental mice. 

Description of Studies

• Study 1 used preclinical techniques, such as cancer cell lines, in mouse models to study ovarian carcinoma and TSC. 
• In Study 2, the anti-seizure potential of PQR620 was evaluated by looking at the seizure threshold in normal and epileptic mice. The activity of PQR620 was compared to existing mTOR inhibitors such as everolimus.

Results

Study 1

• Results from study 1 showed that PQR620 was capable of blocking mTOR activity in a potent manner.
• The drug exhibited anti-tumor properties both in cancer cell lines (in vitro) and in the intact animal (in vivo). 
• The distribution of PQR620 in plasma and brain was promising and indicated it could be beneficial in brain disorders. 

Study 2

• This study showed the penetration of PQR260 in the brain was much more rapid compared to existing clinically used mTOR inhibitors.
• The anti-seizure activity of PQR260 was much more effective in epileptic mice compared to non-epileptic mice.

What does this mean?

• Experiments done in Dr. Löscher’s lab reflect a body of work that led to the characterization of PQR260 in some types of seizure disorders.
• More studies are necessary to confirm these results. However, PQR260 may represent an improvement over existing drugs for conditions where mTOR is over-activated.

References

• Rageot D, et al. Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1] octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders. J Med Chem. 2018 Nov; 61(22):10084-10105.

• Brandt C, et al. The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy. Neuropharmacology. 2018 Sep 15;140:107-120.