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Selective Inhibition of the Hsp90α Isoform
Author(s) -
Mishra Sanket J.,
Khandelwal Anuj,
Banerjee Monimoy,
Balch Maurie,
Peng Shuxia,
Davis Rachel E.,
Merfeld Taylor,
Munthali Vitumbiko,
Deng Junpeng,
Matts Robert L.,
Blagg Brian S. J.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202015422
Subject(s) - gene isoform , hsp90 , heat shock protein , chemistry , biochemistry , protein folding , chaperone (clinical) , folding (dsp implementation) , medicine , gene , pathology , electrical engineering , engineering
The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins contribute to the progression of cancer, and consequently, inhibition of the Hsp90 protein folding machinery represents an innovative approach toward cancer chemotherapy. However, clinical trials with Hsp90 N‐terminal inhibitors have encountered deleterious side effects and toxicities, which appear to result from the pan ‐inhibition of all four Hsp90 isoforms. Therefore, the development of isoform‐selective Hsp90 inhibitors is sought to delineate the pathological role played by each isoform. Herein, we describe a structure‐based approach that was used to design the first Hsp90α‐selective inhibitors, which exhibit >50‐fold selectivity versus other Hsp90 isoforms.