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A Gallium(III) Complex that Engages Protein Disulfide Isomerase A3 (PDIA3) as an Anticancer Target
Author(s) -
Yin HaoYan,
Gao JiuJiao,
Chen Xuemin,
Ma Bin,
Yang ZiShu,
Tang Juan,
Wang BingWu,
Chen Tianfeng,
Wang Chu,
Gao Song,
Zhang JunLong
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202008432
Subject(s) - chemistry , protein disulfide isomerase , endoplasmic reticulum , in vitro , surface plasmon resonance , fluorescence microscope , biophysics , biochemistry , combinatorial chemistry , fluorescence , nanotechnology , biology , materials science , physics , quantum mechanics , nanoparticle
Gallium(III)‐based drugs have gained momentum in cancer therapy due to their iron‐dependent anticancer activity. Judicious choice of ligands is critical for improved oral bioavailability, antitumor efficacy, and distinct mechanisms from simple Ga III salts. We describe Ga III complexes with planar tetradentate salen ligands [salen=2,3‐bis[(4‐dialkylamino‐2‐hydroxybenzylidene)amino]but‐2‐enedinitrile)] and labile axial solvent ligands, which display tumor growth inhibition in vitro and in vivo comparable to cisplatin. Confocal fluorescence microscopy, western blotting, mRNA profiling, chemical proteomics, and surface plasmon resonance (SPR) studies provide compelling evidence that PDIA3, a member of the protein disulfide isomerase (PDI) family involved in endoplasmic reticulum (ER) stress, is a direct target of Ga‐1 . This work offers a new route to designing and synthesizing Ga‐based drugs, and also reveals that PDIA3 is an important anticancer target.