Dactolisib is a dual inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) and is considered an attractive agent for treatment of polycystic kidney disease.
Inhibition of mammalian target of rapamycin (mTOR) slows polycystic kidney disease (PKD) progression in animal models, but randomized controlled trials failed to prove efficacy of mTOR inhibitor treatment.
Although mutations in the PI3K/AKT/mTOR pathway are highly characterized in cancer, recent evidence indicates that alterations in the proliferative signals are major drivers of other diseases such as overgrowth disorders and polycystic kidney disease.
Mammalian target of rapamycin (mTOR) is an evolutionarily conserved protein kinase. mTOR forms two distinct functional multiprotein kinase complexes that mutually phosphorylate different substrates and regulate a wide array of essential cellular processes including translation, transcription and autophagy. mTOR is active in several types of cancer and plays a role in a variety of other serious human diseases, including diabetes, neurodegenerative disorders and polycystic kidney disease.
Sirolimus, an inhibitor of the protein kinase mammalian target of rapamycin (mTOR) and a potent anti-proliferative agent, decreases cyst growth in several genetically distinct rodent models of polycystic kidney disease (PKD).
Aberrant activation of the mammalian target of rapamycin (mTOR) pathway occurs in polycystic kidney disease (PKD). mTOR inhibitors, such as rapamycin, are highly effective in several rodent models of PKD, but these models result from mutations in genes other than Pkd1 and Pkd2, which are the primary genes responsible for human autosomal dominant PKD.