A scaffold merging approach to Hsp90 C-terminal inhibition: synthesis and evaluation of a chimeric library??

MedChemComm Pub Date: 2017-01-13 DOI: 10.1039/C6MD00377J

Abstract

Inhibition of the Hsp90 C-terminus is an attractive therapeutic paradigm for the treatment of cancer, however the developmental space of C-terminal inhibitors is limited. It was hypothesized that the combination of two previously identified scaffolds into a single structure could provide a platform for which to probe the three-dimensional space within the Hsp90 C-terminal binding pocket. The resulting chimeric compounds displayed anti-proliferative activity at low micromolar concentrations and manifested inhibitory activity in an Hsp90-dependent rematuration assay. Initial structure–activity relationships suggest that this new scaffold binds Hsp90 in a conformation different from that of the parent compounds, and consequently, provides a new opportunity to develop more efficacious inhibitors of the Hsp90 C-terminal binding pocket.

Graphical abstract: A scaffold merging approach to Hsp90 C-terminal inhibition: synthesis and evaluation of a chimeric library
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