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long-term treatment in certain cell types.
34,35
The mechanisms whereby
mTORC2 is generally unresponsive to rapamycin, either due to steric hindrance
to binding at the FKBP12-rapamycin binding (FRB) domain or another
mechanism, is unknown at this time.
Any structural changes to the rapamycin scaffold can affect binding to
mTOR both directly and indirectly as a function of binding to FKBP12.
36,37
In
fact, the interaction of the rapamycin-FKBP12 complex with mTOR correlates
well with the conformational flexibility of the so-called effector domain of
rapamycin. This domain consists of regions of the molecule that make
important hydrophobic interactions with the FRB domain of mTOR, and
consists principally of the triene region (C17 to C22) of rapamycin and a
number of methyl groups, notably the OMe group at C16, and the methyls
attached to C23, C29, and C31.
38,39
Thus, modifications that change the global
conformation of the macrolide ring can have ''non-linear'' or unpredictable
effects on binding. Structure-activity relationship (SAR) determinations for
rapamycin analogs can therefore be problematic.
Nonetheless, a number of useful correlates between structure and activity
have been observed by a number of groups working in this area and have been
reviewed elsewhere.
40
The vast majority of rapamycin analogs exhibit
decreased FKBP12 binding anity, mTOR inhibition, or both. Rapamycin
analogs that have been approved for human use or are currently in clinical
trials (Figure 14.3) are modified at the C40 hydroxyl and generally show
improvement in pharmacokinetic parameters. Modification at this position
(that is relatively solvent exposed in the FKBP12-rapamycin-mTOR com-
plex)
38
has proven a useful route to potent compounds that are further
optimized for drug-like properties (i.e. solubility, pharmacokinetics). These
currently include temsirolimus (CCI-779, Torisel
s
),
41
everolimus (RAD001,
Anitor
s
),
42
zotarolimus (ABT-578),
43-45
and ridaforolimus (deforolimus,
AP23573, MK-8669).
46
14.3 Immunophilin Screening and Cell-based
Approaches to Identify Candidates for Pre-clinical
Evaluation
Rapamycin and FK-506 have also been reported to exhibit neuroprotective
activity in vitro
47
that has been attributed to FKBP binding
48
rather than
mTOR inhibition. However, it had also been demonstrated that while the
immunophilin ligand FK-506 showed ecacy in a rodent model of ischemic
stroke,
49
rapamycin had no effect in this model, suggesting that immunophilin
binding may only play a partial role in neuroprotection/neuroregeneration.
Non-immunosuppressive immunophilin ligands—such as GPI-1046 (Figure
14.4), which contains the FKBP-binding moiety of rapamycin and FK-506 but
lacks an mTOR or calcineurin binding domain—have been pursued as
potential therapies for neurodegenerative disorders.
50
However, the neuro-
protective activity of GPI-1046 is marginal in both neurite outgrowth studies in
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