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Moreover, many natural product structures are vital tool compounds in deci-
phering signaling pathways within the cell. Our approach has therefore been to
attempt to modulate the activity of a medically useful natural product in order
to perturb biological activity towards a desired profile, while at the same time
learning how structural changes affect mechanism. With such an approach, and
using cell-based methods for screening, we hoped to obtain novel structures
with a unique activity profile that could serve both as clinical candidates and
tools to explore disease biology.
57
Specifically, our work supports the hypothesis that modification of rapa-
mycin at the mTOR binding region can provide non-immunosuppressive
compounds with potent neuroprotective activity, and significant ecacy in an
animal model of ischemic stroke. The role of natural products as privileged
scaffolds for semi-synthesis has been under-explored in recent years, but
remains a useful complement to modern approaches to medicinal chemistry.
Combined with cell-based screening, the preparation of biologically active
rapamycin analogs has yielded a clinical candidate, ILS-920. Preliminary
explorations of the chemical biology of the compound suggest that the in vivo
ecacy of ILS-920 derives from the compound's dual functions as a potential
activator of glucocorticoid and other steroid receptors via dissociation of
FKBP52 from the receptor complexes, and as an inhibitor of L-type voltage-
gated Ca
21
channels via binding to the b1 subunit.
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