Divergent synthesis of a pochonin library targeting HSP90 and in vivo efficacy of an identified inhibitor.

The heat shock protein 90 (HSP90) has emerged as one of the most exciting therapeutic target in recent years.[1, 2] Despite the seemingly ubiquitous function of this constitutively expressed chaperone, its role in stabilizing conformationally labile proteins has implications in pathologies ranging from oncology to neurodegenerative diseases. Most of HSP90’s endogenous clients[3] are key regulators of cell signaling which are destabilized and degraded in the absence of HSP90’s chaperoning activity. The dependence of transformed cells on HSP90 is further heightened by the fact that many oncogenic mutations, while increasing the activity of pro-growth signaling pathways, are less stable than their wild type counterpart and have an increased dependence on HSP90’s chaperoning activity.[4] A clinically relevant example is the heightened dependence of drug resistant Bcr-Abl mutants on HSP90’s activity and the fact that HSP90 inhibitors in combination with Abl inhibitors remain effective against such mutants.[5, 6] Accordingly, HSP90 inhibition provides a broad and effective target for anticancer treatment. Furthermore, HSP90 inhibitors can act synergistically with a cytotoxic agent.[7] HSP90 is also implicated in regulating the fate of a number of conformationally unstable proteins which underlie the development of neurodegenerative diseases.[8] It has been shown that HSP90 inhibitors can reduce protein aggregates in cellular and animal models of Huntington disease,[9] spinal and bulbar muscular atrophy,[10] Parkinson disease,[11] and other Tau protein-related neurodegenerative diseases.[12]