Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors

Hsp90 chaperones play a critical role in modulating the activity of many cell signaling proteins and are an attractive target for anti-cancer therapeutics. We report here the structures of the water soluble 8-aryl-sulfanyl adenine class Hsp90 inhibitors, 1 (PU-H71) and 2 (PU-H64), in complex with the N-terminal domain of human Hsp90α. The conformation of 1 when bound to Hsp90 differs from previously reported 8-aryl adenine Hsp90 inhibitors including 3 (PU24FCl). While the binding mode for 3 places the 2′-halide of the 8-aryl group on top of the adenine ring, for 1 and 2, we show that the 2′-halide is rotated approximately 180° away. This difference explains the opposing trends in Hsp90 inhibitory activity for the 2′-halo derivatives of the 3′,4′,5′-trimethoxy series where Cl > Br > I compared to the 4′,5′-methylenedioxy series where I > Br > Cl. We also present quantum chemical calculations of 2 and its analogues that illuminate their basis for Hsp90 inhibition. The calculated conformation of 2 agreed well with the crystallographically observed conformations of 1 and 2. The predictive nature of the calculations has allowed the exploration of additional derivatives based on the 8-aryl adenine scaffold.