Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 59, Issue 45, Pages 20147-20153Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202008432
Keywords
anticancer compounds; chemoproteomics; gallium; metallodrugs; Salen ligands
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Funding
- National Key Basic Research Support Foundation of China [2015CB856301]
- National Scientific Foundation of China (NSFC) [21571007, 21621061, 21778002, 21861162008]
- National Key Research and Development Projects [2016YFA0501500]
- National Natural Science Foundation of China [21925701, 91953109, 21521004]
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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 ofGa-1. This work offers a new route to designing and synthesizing Ga-based drugs, and also reveals that PDIA3 is an important anticancer target.
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