Catalytic mammalian target of rapamycin inhibitors as antineoplastic agents

Abstract

The mammalian target of rapamycin (mTOR) pathway is a major therapeutic target in the treatment of hematological malignancies, as it controls cellular events of high importance for regulation of mRNA translation and protein production. Rapalogs, or first-generation mTOR inhibitors, have produced only modest clinical benefits so far. Limitations to rapalogs likely result from the partial inhibition of mTORC1 substrates and lack of effects on mTORC2. Efforts toward the development of agents with more potent and complete inhibitory effects on the mTOR pathway have resulted in the development of catalytic mTOR inhibitors. Key preclinical and early clinical investigations of several catalytic mTOR inhibitors and potential resistance mechanisms to their activities are summarized here.

mTOR signaling in the neuropathophysiology of depression: current evidence

“…Conversely, mTORC2 is relatively resistant to rapamycin, and prolonged treatment is required for rapamycin to inhibit the activity of mTORC2. 35 Rapamycin inhibits the P70S6K and 4E-BP1 phosphorylation, thus reducing transcription and translation of protein mediated by mTOR signaling. It prevents mTOR from further phosphorylation of P70S6K, 4E-BP1, thus indirectly decreasing the proteins involved in transcription and translation of this signaling.…”