An Hsp90 modulator that exhibits a unique mechanistic profile

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Ramsey, Deborah M.¹  McConnell, Jeanette R.¹  Alexander, Leslie D.²  Tanaka, Kaishin W.¹  Vera, Chester M.¹  McAlpine, Shelli R.¹ 

[1] Univ New S Wales, Dept Chem, Sydney, NSW 2052, Australia

[2] San Diego State Univ, Dept Chem & Biochem, San Diego, CA 92182 USA

关键词: Hsp90;    Sansalvamide A;    Pull-down;    Caspase 3;    Heat shock proteins;   

DOI  :  10.1016/j.bmcl.2012.03.012

来源: Elsevier

【 摘 要 】

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. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

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