Brain-penetrant PQR620 mTOR and PQR530 PI3K/mTOR inhibitor reduce huntingtin levels in cell models of HD

Neuropharmacology. 2020 Jan 1:162:107812. doi: 10.1016/j.neuropharm.2019.107812. Epub 2019 Oct 14.


One of the pathological hallmarks of Huntington disease (HD) is accumulation of the disease-causing mutant huntingtin (mHTT), which leads to the disruption of a variety of cellular functions, ultimately resulting in cell death. Induction of autophagy, for example by the inhibition of mechanistic target of rapamycin (mTOR) signaling, has been shown to reduce HTT levels and aggregates. While rapalogs like rapamycin allosterically inhibit the mTOR complex 1 (TORC1), ATP-competitive mTOR inhibitors suppress activities of TORC1 and TORC2 and have been shown to be more efficient in inducing autophagy and reducing protein levels and aggregates than rapalogs. The ability to cross the blood-brain barrier of first generation catalytic mTOR inhibitors has so far been limited, and therefore sufficient target coverage in the brain could not be reached. Two novel, brain penetrant compounds - the mTORC1/2 inhibitor PQR620, and the dual pan-phosphoinositide 3-kinase (PI3K) and mTORC1/2 kinase inhibitor PQR530 - were evaluated by assessing their potential to induce autophagy and reducing mHTT levels. For this purpose, expression levels of autophagic markers and well-defined mTOR targets were analyzed in STHdh cells and HEK293T cells and in mouse brains. Both compounds potently inhibited mTOR signaling in cell models as well as in mouse brain. As proof of principle, reduction of aggregates and levels of soluble mHTT were demonstrated upon treatment with both compounds. Originally developed for cancer treatment, these second generation mTORC1/2 and PI3K/mTOR inhibitors show brain penetrance and efficacy in cell models of HD, making them candidate molecules for further investigations in HD.

Keywords: Aggregation; Catalytic mTOR inhibition; Huntingtin; Huntington disease; Neurodegeneration.

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Azabicyclo Compounds / pharmacology*
  • Blood-Brain Barrier
  • Cell Line
  • Corpus Striatum / cytology
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Huntingtin Protein / drug effects*
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors
  • Mice
  • Morpholines / pharmacology*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Phosphatidylinositol 3-Kinases
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Protein Aggregates / drug effects*
  • Pyridines / pharmacology*
  • Triazines / pharmacology*


  • Azabicyclo Compounds
  • Enzyme Inhibitors
  • Huntingtin Protein
  • Morpholines
  • PQR530
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Aggregates
  • Pyridines
  • Triazines
  • pqr620
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2