Synthesis and Biological Evaluation of a New Class of Geldanamycin Derivatives as Potent Inhibitors of Hsp90
摘要:
The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt; followed by their proteasomal degradation. Rsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage For cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft; models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and areas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.
Synthesis and Biological Evaluation of a New Class of Geldanamycin Derivatives as Potent Inhibitors of Hsp90
作者:Jean-Yves Le Brazidec、Adeela Kamal、David Busch、Lia Thao、Lin Zhang、Gregg Timony、Roy Grecko、Katy Trent、Rachel Lough、Tim Salazar、Samina Khan、Francis Burrows、Marcus F. Boehm
DOI:10.1021/jm0306125
日期:2004.7.1
The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt; followed by their proteasomal degradation. Rsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage For cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft; models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and areas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.