Contemporary mTOR inhibitor scaffolds to diseases breakdown: A patent review (2015-2021)

Mechanistic target of rapamycin (mTOR) is a highly conserved protein kinase acting as a central regulator of cell functions. The kinase forms two distinct mTOR complexes termed as mTORC1 and mTORC2. Dysregulation of mTOR activity is associated with various pathological conditions. Inhibition of overactivated mTOR represent a rational approach in the treatment of numerous human diseases. Rapamycin is a potent natural inhibitor of mTOR exhibiting significant antitumor and immunosuppressive activity. Derivatization of rapamycin provided rapalogs, the first generation of mTOR inhibitors that selectively inhibit mTORC1 activity. Further interest of research community resulted in creation of the second generation of mTOR inhibitors involving both, mTOR kinase inhibitors and dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitors. Recently, combining advances of first and second generation of mTOR inhibitors yielded in the third generation of inhibitors termed as rapalinks. Nowadays, novel inhibitors belonging to all of the three generations are still under development. These inhibitors help us better to understand role of mTOR in mTOR signaling pathway as well as in diverse human diseases. In this review, we summarize recent reported mTOR inhibitors or methods of use thereof in the treatment of various diseases.