Uncoupling neuroprotection from immunosuppression: The discovery of ILS-920

The family of natural product immunophilin ligand macrolides (exemplified by rapamycin, FK506, meridamycin, and antascomicin) all contain a pipecolic acid- tricarbonyl motif (required for binding to immunophilins or cyclophilins) and a variable polyketide portion.  In two of the four compounds (rapamycin/FK506), this variable polyketide portion confers an exquisitely specific binding affinity for a second protein, leading to formation of a protein-ligand-protein ternary complex.  For example, the rapamycin-FK505 binding protein (FKBP)12 complex recruits the mammalian target of rapamycin (mTOR) kinase, and the subsequent inhibition of kinase activity leads to inhibition of cell proliferation that has important application in transplantation and oncology.

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) equity, 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 yielded ILS-920, a compound that advanced into human trials for stroke.  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.