The second generation of mTOR inhibitors is known as ATP-competitive mTOR kinase inhibitors. mTORC1/mTORC2 dual inhibitors such as torin-1, torin-2 and vistusertib, are designed to compete with ATP in the catalytic site of mTOR. They inhibit all of the kinase-dependent functions of mTORC1 and mTORC2 and block the feedback activation of PI3K/AKT signaling, unlike rapalogs, which only target mTORC1. Development of these drugs has reached clinical trials, although some, such as vistusertib, have been discontinued. Like rapalogs, they decrease protein translation, attenuate cell cycle progression, and inhibit angiogenesis in many cancer cell lines and also in human cancer. In fact, they have been proven to be more potent than rapalogs.
Theoretically, the most important advantages of these mTOR inhibitors is the considerable decrease of AKT phosphorylation on mTORC2 blockade and in addition to a better inhibition on mTORC1. However, some drawbacks exist. Even though these compounds have been effective in rapamycin-insensitive cell lines, they have only shown limited success in KRAS driven tumors. This suggests that combinational therapy may be necessary for the treatment of these cancers. Another drawback is also their potential toxicity. These facts have raised concerns about the long term efficacy of these types of inhibitors.
The close interaction of mTOR with the PI3K pathway has also led to the development of mTOR/PI3K dual inhibitors. Compared with drugs that inhibit either mTORC1 or PI3K, these drugs have the benefit of inhibiting mTORC1, mTORC2, and all the catalytic isoforms of PI3K. Targeting both kinases at the same time reduces the upregulation of PI3K, which is typically produced with an inhibition on mTORC1. The inhibition of the PI3K/mTOR pathway has been shown to potently block proliferation by inducing G1 arrest in different tumor cell lines. Strong induction of apoptosis and autophagy has also been seen. Despite good promising results, there are preclinical evidence that some types of cancers may be insensitive to this dual inhibition. The dual PI3K/mTOR inhibitors are also likely to have increased toxicity.