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Bioorg Med Chem Lett. 2012 May 1;22(9):3287-90. doi: 10.1016/j.bmcl.2012.03.012. Epub 2012 Mar 11.

An Hsp90 modulator that exhibits a unique mechanistic profile.

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1
Department of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.

Abstract

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.

PMID:
22480433
PMCID:
PMC3337333
DOI:
10.1016/j.bmcl.2012.03.012
[Indexed for MEDLINE]
Free PMC Article
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