4-Amino derivatives of the Hsp90 inhibitor CCT018159

Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure–activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.

Graphical abstractNovel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 have been prepared and the observed SAR explained by X-ray co-crystallography with Human Hsp90. The most potent of the new compounds has an IC50 of less than 600 nM against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.Figure optionsDownload full-size imageDownload as PowerPoint slide