Current development of the second generation of mTOR inhibitors as anticancer agents

Abstract

The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, acts as a "master switch" for cellular anabolic and catabolic processes, regulating the rate of cell growth and proliferation. Dysregulation of the mTOR signaling pathway occurs frequently in a variety of human tumors, and thus, mTOR has emerged as an important target for the design of anticancer agents. mTOR is found in two distinct multiprotein complexes within cells, mTORC1 and mTORC2. These two complexes consist of unique mTOR-interacting proteins and are regulated by different mechanisms. Enormous advances have been made in the development of drugs known as mTOR inhibitors. Rapamycin, the first defined inhibitor of mTOR, showed effectiveness as an anticancer agent in various preclinical models. Rapamycin analogues (rapalogs) with better pharmacologic properties have been developed. However, the clinical success of rapalogs has been limited to a few types of cancer. The discovery that mTORC2 directly phosphorylates Akt, an important survival kinase, adds new insight into the role of mTORC2 in cancer. This novel finding prompted efforts to develop the second generation of mTOR inhibitors that are able to target both mTORC1 and mTORC2. Here, we review the recent advances in the mTOR field and focus specifically on the current development of the second generation of mTOR inhibitors as anticancer agents.

Figure 1.. Schematic structure of mTOR.

The N-terminus of mTOR contains two tandemly repeated HEAT motifs. Downstream of the HEAT repeat region lies a FAT domain, an FRB domain, a catalytic kinase domain, an auto-inhibitory repressor domain, and a C-terminal FATC domain. The first generation of mTOR inhibitors (rapalogs) bind to FRB domain, whereas the second generation of mTOR inhibitors target the kinase domain.

Figure 2.. A model of mTOR signaling network.

mTOR signaling regulates multiple cellular processes by sensing nutrients, growth factors, energy, and stress. Arrows represent activation, whereas bars represent inhibition.