Mammalian Target Of Rapamycin Inhibitors

The chemical structures of the mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are shown in Fig. 3. Both are macrocyclic lactones. Sirolimus (also known as rapamycin) is a lipophilic molecule (molecular weight of 914) derived from Streptomyces hygroscopicus. This actinomycete fermentation product was identified in the early 1970s and was approved by the FDA in 1999 for use with CsA to reduce the incidence of acute rejection in renal transplantation (126). Everolimus is a

Fig. 3. Chemical structures of the mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus. This figure was published in Critical Reviews in Oncology/Hematology, Volume 56, Taylor AL, Watson CJE, Bradley JA, Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy, page 34, Copyright Elsevier 2005.

Fig. 3. Chemical structures of the mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus. This figure was published in Critical Reviews in Oncology/Hematology, Volume 56, Taylor AL, Watson CJE, Bradley JA, Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy, page 34, Copyright Elsevier 2005.

chemically modified version that is more hydrophilic than sirolimus and has improved pharmacokinetic characteristics and improved bioavailability (127). Everolimus is still in phase III trials and is only available for investigational use in the USA.

Sirolimus and everolimus readily cross the lymphocyte plasma membrane and bind to the intracellular immunophilin, FK506-binding protein-12 (128). In contrast to tacrolimus, sirolimus-immunophilin and everolimus-immunophilin complexes do not inhibit calcineurin activity. Instead, the complexes are highly specific inhibitors of the mTOR, a cell cycle serine/threonine kinase involved in the protein kinase B-signaling pathway. This results in suppressed cytokine-induced T-lymphocyte proliferation, with a block in progression from the G1 to S phase of the cell cycle (129). The mTOR inhibitors work synergistically with the calcineurin inhibitors to produce a profound immunosuppressive effect on T lymphocytes.

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