Crystal structures of human HSP90a-complexed with dihydroxyphenylpyrazoles

A series of dihydroxyphenylpyrazole compounds were identified as a unique class of reversible Hsp90 inhibitors. The crystal structures for two of the identified compounds complexed with the N-terminal ATP binding domain of human Hsp90a were determined. The dihydroxyphenyl ring of the compounds fits deeply into the adenine binding pocket with the C2 hydroxyl group forming a direct hydrogen bond with the side chain of Asp93. The pyrazole ring forms hydrogen bonds to the backbone carbonyl of Gly97, the hydroxyl group of Thr184 and to a water molecule, which is present in all of the published HSP90 structures. One of the identified compounds (G3130) demonstrated cellular activities (in Her-2 degradation and activation of Hsp70 promoter) consistent with the inhibition of cellular Hsp90 functions. 2005 Elsevier Ltd. All rights reserved. Heat-shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone required for the stability and function of a number of client proteins, some of them, such as Akt, Her2, and HIF-1alpha, play important roles in promoting cancer cells growth and/or survival. Several Hsp90 inhibitors including the natural products geldanamycin, radicicol and their derivatives (e.g., 17desmethoxy-17-N,N-dimethylaminoethylamino-geldanamycin (17-DMAG) and 17-allylamino-17-demethoxygeldanamycin (17-AAG)), as well as purinepyrazole-, and imidazopyrazine-based small molecule synthetic compounds have been identified. The crystal structures for geldanamycin, radicicol, and purine derivatives complexed with the N-terminal ATP-binding domain of Hsp90 have been reported revealing a critical Asp residue at the bottom of the pocket for ligand binding. Treatment of tumor cells with Hsp90 inhibitors causes selective degradation of Hsp90 client proteins and cell growth arrest and/or apoptosis in a number of cancer cell lines. It has been reported that the binding affinities of 17-AAG and a purine derivative, PU24FCL are much higher for tumor-derived HSP90 than for HSP90 0960-894X/$ see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.12.087