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An Hsp90 modulator that exhibits a unique mechanistic profile. | LitMetric

Described is the synthesis of two biotinylated derivatives of a cytotoxic macrocycle. Pull-down assays indicate that this macrocycle targets the N-middle domain of Hsp90. Untagged compound can effectively compete away tagged compound-Hsp90 protein complexes, confirming the binding specificity of the macrocycle for Hsp90. The macrocycle is similar in potency to other structurally-related analogs of Sansalvamide A (San A) and induces apoptosis via a caspase 3 mechanism. Unlike other San A derivatives, we show that the macrocycle does not inhibit binding between C-terminal client proteins and co-chaperones and Hsp90, suggesting that it has a unique mechanism of action.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337333PMC
http://dx.doi.org/10.1016/j.bmcl.2012.03.012DOI Listing

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