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Ritterostatin G N 1 N , a Cephalostatin–Ritterazine Bis‐steroidal Pyrazine Hybrid, Selectively Targets GRP78
Author(s) -
Ambrose Andrew J.,
Santos Evelyne A.,
Jimenez Paula C.,
Rocha Danilo D.,
Wilke Diego V.,
Beuzer Paolo,
Axelrod Josh,
Kumar Kanduluru Ananda,
Fuchs Philip L.,
Cang Hu,
CostaLotufo Letícia V.,
Chapman Eli,
La Clair James J.
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600669
Subject(s) - endoplasmic reticulum , gene isoform , cytotoxic t cell , pyrazine , mode of action , drug discovery , cell culture , biological activity , chemistry , unfolded protein response , programmed cell death , apoptosis , microbiology and biotechnology , biology , computational biology , biochemistry , gene , stereochemistry , in vitro , genetics
Natural products discovered by using agnostic approaches, unlike rationally designed leads or those obtained through high‐throughput screening, offer the ability to reveal new biological pathways and, hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine–cephalostatin family of natural products displays robust and potent antitumor activities, with sub‐nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we used comparative cellular and molecular biological methods to uncover the ritterazine–cephalostatin cytotoxic mode of action (MOA) in human tumor cells. Our findings indicated that, whereas ritterostatin G N 1 N , a cephalostatin–ritterazine hybrid, binds to multiple HSP70s, its cellular trafficking confines activity to the endoplasmic reticulum (ER)‐based HSP70 isoform, GRP78. This targeting results in activation of the unfolding protein response (UPR) and subsequent apoptotic cell death.