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• W2406402893 abstract "Natural product scaffolds are privileged structures that have withstood the pressures of eons of natural selection and have demonstrated utility in human medicine. They therefore represent a potential bridge to balancing risk and innovation in drug discovery and can complement modern synthetic approaches to medicinal chemistry. Our team explored modulating the activity of a medically useful natural product in order to modulate this activity towards a desired profile, while at the same time learning how structural changes affect mechanism, employing contemporary tools of chemical biology. Rapamycin is an immunosuppressive natural product inhibitor of mammalian target of rapamycin (mTOR). We tested the hypothesis that modification of rapamycin at the mTOR binding region could provide non-immunosuppressive compounds with potent neuroprotective activity and significant efficacy in an animal model of ischemic stroke. Employing cell-based screening of our existing rapamycin analog (rapalog) collection, we identified Diels-Alder adduct formation at the C19,C22 diene as a potential synthetic strategy. The subsequent preparation of biologically active, non-immunosuppressive rapalogs has yielded a clinical compound, ILS-920. Preliminary investigations of the chemical biology of the compound suggest that the in vivo efficacy of ILS-920 derives from the compound’s dual functions as a potential activator of glucocorticoid and other steroid receptors via dissociation of FK506 binding protein 52 (FKBP52) from the receptor complexes, and as an inhibitor of L-type voltage gated Ca2+ channels via binding to the β1 subunit." @default.
• W2406402893 created "2016-06-24" @default.
• W2406402893 creator A5075387164 @default.
• W2406402893 date "2010-09-30" @default.
• W2406402893 modified "2023-09-23" @default.
• W2406402893 title "Uncoupling Neuroprotection from Immunosuppression: the Discovery of ILS-920" @default.
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• W2406402893 doi "https://doi.org/10.1039/9781849731980-00316" @default.
• W2406402893 hasPublicationYear "2010" @default.
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