TY - JOUR
T1 - Enniatin A Analogues as Novel Hsp90 Inhibitors that Modulate Triple-Negative Breast Cancer
AU - Serwetnyk, Michael A.
AU - Crowley, Vincent M.
AU - Brackett, Christopher M.
AU - Carter, Trever R.
AU - Elahi, Asif
AU - Kommalapati, Vamsi Krishna
AU - Chadli, Ahmed
AU - Blagg, Brian S.J.
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/12/14
Y1 - 2023/12/14
N2 - The 90 kilo-Dalton heat shock protein (Hsp90) is a molecular chaperone that facilitates the maturation of nascent polypeptides into their biologically active conformation. Because many of the >400 known client protein substrates are implicated in the development/progression of cancer, it is hypothesized that Hsp90 inhibition will simultaneously shut down numerous oncogenic pathways. Unfortunately, most of the small molecule Hsp90 inhibitors that have undergone clinical evaluation thus far have failed due to various toxicities. Therefore, the disruption of Hsp90 protein-protein interactions with cochaperones and/or client substrates has been proposed as an alternative way to achieve Hsp90 inhibition without such adverse events. The hexadepsipeptide Enniatin A (EnnA) has recently been reported to be one such inhibitor that also manifests immunogenic activity. Herein, we report preliminary structure-activity relationship (SAR) studies to determine the structural features that confer this unprecedented activity for an Hsp90 inhibitor. Our studies find that EnnA’s branching moieties are necessary for its activity, but some structural modifications are tolerated.
AB - The 90 kilo-Dalton heat shock protein (Hsp90) is a molecular chaperone that facilitates the maturation of nascent polypeptides into their biologically active conformation. Because many of the >400 known client protein substrates are implicated in the development/progression of cancer, it is hypothesized that Hsp90 inhibition will simultaneously shut down numerous oncogenic pathways. Unfortunately, most of the small molecule Hsp90 inhibitors that have undergone clinical evaluation thus far have failed due to various toxicities. Therefore, the disruption of Hsp90 protein-protein interactions with cochaperones and/or client substrates has been proposed as an alternative way to achieve Hsp90 inhibition without such adverse events. The hexadepsipeptide Enniatin A (EnnA) has recently been reported to be one such inhibitor that also manifests immunogenic activity. Herein, we report preliminary structure-activity relationship (SAR) studies to determine the structural features that confer this unprecedented activity for an Hsp90 inhibitor. Our studies find that EnnA’s branching moieties are necessary for its activity, but some structural modifications are tolerated.
KW - Enniatin A
KW - Hsp90
KW - Protein−protein interactions
KW - Structure−activity relationships
KW - Triple-negative breast cancer
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U2 - 10.1021/acsmedchemlett.3c00423
DO - 10.1021/acsmedchemlett.3c00423
M3 - Article
AN - SCOPUS:85179161591
SN - 1948-5875
VL - 14
SP - 1785
EP - 1790
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 12
ER -