Rapamycin different activity

Insulin and other growth factors result in the phosphorylation of BP-1 at five unique sites. Phosphorylation of BP-1 results in its dissociation from 4E, and it cannot rebind until critical sites are dephosphorylated. The protein kinase responsible has not been identified, but it appears to be different from the one that phos-phorylates 4E. A kinase in the mammalian target of rapamycin (mTOR) pathway, perhaps mTOR itself, is involved. These effects on the activation of 4E explain in part how insuhn causes a marked posttranscriptional... 

Another approach to the management of IM resistance is to combine agents that are individually active against CML but have differing mechanisms of action that may allow either additive or synergistic effects in a non-cross-resistant marmer. This approach has been extensively studied in the literature and will not be reviewed in detail here. An excellent discussion of combination therapy is foimd in the reviews by Hochhaus and La Rosee (52,85). Some combination approaches have utilized famesyl transferase inhibition such as lonafamib in combination with IM, inhibitors of the mammalian target of rapamycin (mTOR) in combination with IM and combining mycophenolic acid, an inhibitor of the JAK-STAT pathway. 

A new class of immunosuppressive agents called proliferation-signal inhibitors (PSIs) includes sirolimus (rapamycin) and its derivative everolimus. The mechanism of action of PSIs differs from that of the calcineurin inhibitors. PSIs bind the circulating immunophilin FK506-binding protein 12, resulting in an active complex that blocks the molecular target of rapamycin (mTOR). 

An intriguing new development relates to conditional protein splicing [27]. In this scenario the property of the immunosuppressant rapamycin is utilized to bind simultaneously to two different proteins (FKBP and FRB) with high affinity. If FKBP and FRB are linked to the N- and C-termini of the intein-extein halves (see Fig. 4 for the protein constructs) the addition of rapamycin would trigger the formation of a ternary complex, thereby bringing the intein halves into close proximity. In a consecutive reaction the two exteins can combine to generate an active or, e.g., fluorescent labeled protein. Since both halves can be expressed in mammalian and other cells, cellular functions can be studied. 

Even if the only difference between the two alkenes is the number of substituents, that can be enough for some reactions. If the substituents are simple alkyl or aryl groups, then the more highly substituted alkene will be the more nucleophilic. This is enough to allow the epoxidation of the trisubstituted alkene in citronellene2 28 while leaving the monosubstituted alkene intact and provide a source of the optically active acid 31 for Nicolaou s synthesis of rapamycin.3... 

FK506 (tacrolimus) (23) is a 23-membered macrocyclic lactone isolated from Streptomyces tsukubaensis and is structurally related to rapamycin. It displays antifungal and immunosuppressive activities. It is marketed as an immunosuppressant that can be used in transplant therapy and several autoimmune disorders. Rapamycin and FK506 share the same common cellular receptor FKBP, but they present a different mechanism of action. Similar to cyclosporine A, FK506 suppresses T-cell activation at the level of lymphokine production and prevents the expression of the interleukin 2 receptor (IL-2R). ... 

Fig. 1. The structure of cyclosporin A (CsA), FK506, rapamycin, and FK506 s derivatives. Note the common structural features of FK506, rapamycin, GPI-1046 and V-10,367, while CsA has an entirely different chemical stracture. Despite their structural differences, CsA and FK506, as immunosuppressants, exhibit a nearly identical spectrum of action on T lymphocytes. In contrast, regardless of their stractural similarity, FK506 and rapamycin exhibit quite different spectra of action on T lymphocytes, though both FK506 and rapamycin are powerful immunosuppressants. GPI-1046 and V-10,367 do not have any immunosuppressive activity however, they have neurotrophic activities as do FK506 and rapamycin.

However, some preliminary results show that rapamycin is also not devoid of side effects. The major toxicides associated with rapamycin treatment include thrombocytopenia and hyperlipidemia [23]. Nonetheless, it is of great interest that its action on lymphocytes is quite different from those of FK506 and CsA. FK506 and CsA mediate their inhibition of cytokine transcription early in the G, phase during T-cell activation, whereas rapamycin exhibits its inhibitory effects on the proliferation of T cells at the G/S transition of the cell cycle induced by cytokines. Thus, the events that are blocked by FK506/CsA and rapamycin are independent, but sequentially related in the signaling pathway that follows T-cell activation (Fig. 4) [24]. 

Everolimus is an orally active, semisynthetic 40-O-(2-hydroxyethyl) derivative of rapamycin (also known as sirolimus) and was originally obtained from Streptomyces hygroscopicus. Everolimus is a proliferation inhibitor that blocks growth factor-mediated signal transduction and prevents organ rejection through a different mechanism than mycophenoliate mofetil (81). 

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