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An Antitumor Bis(N‐Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target
Author(s) -
Hu Di,
Yang Chen,
Lok ChunNam,
Xing Fangrong,
Lee PuiYan,
Fung Yi Man Eva,
Jiang Haibo,
Che ChiMing
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201904131
Subject(s) - asparagine , cisplatin , chemistry , cancer cell , dna , platinum , adduct , asparagine synthetase , biochemistry , cancer research , enzyme , cancer , chemotherapy , biology , genetics , catalysis , organic chemistry
New anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe a rare example of an antitumor Pt II complex targeting a tumor‐associated protein, rather than DNA, under cellular conditions. Complex [(bis‐NHC)Pt(bt)]PF 6 ( 1 a ; Hbt=1‐(3‐hydroxybenzo[b]thiophen‐2‐yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry. An unbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as a molecular target of 1 a . Accordingly, 1 a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. A bis‐NHC‐ligated Pt species generated from the hydrolysis of 1 a forms adducts with thiols and appears to target an active‐site cysteine of ASNS.