Biased Antagonists of CXCR4 Avoid the Development of Antagonist Tolerance

Despite reported tolerance to antagonists of multiple GPCRs, very few studies provide mechanistic insight and strategies to avoid it [50, 133, 134]. Tolerance to the only FDA–approved CXCR4 receptor antagonist AMD3100 can occur and significantly limits the potential to target the receptor in a variety of pathologies [50]. This tolerance is associated with increased receptor expression on the cell surface. In this thesis, we have investigated the mechanism of tolerance to AMD3100 and developed strategies to avoid it. We hypothesize that accumulation of CXCR4 on the cell surface leads to the development of tolerance, at least in part, due to the inhibition of receptor endocytosis by AMD3100. Thus, we hypothesized that antagonists that inhibited G protein signalling but not receptor endocytosis would avoid the development of tolerance. Few compounds of this type, called biased antagonists, have been discovered [135, 136]. By understanding the mechanisms through which tolerance develops, we believe that future pharmaceutical development will benefit from rational design of inhibitors that avoid these processes.