An Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target

Di Hu, Chen Yang, Chun-Nam Lok, Fangrong Xing, Pui-Yan Lee, Yi Man Eva Fung, Haibo Jiang, Chi-Ming Che

Research output: Contribution to journalArticlepeer-review

25 Citations (Web of Science)

Abstract

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)]PF6 (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.

Original languageEnglish
Pages (from-to)10914-10918
Number of pages6
JournalANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume58
Issue number32
DOIs
Publication statusPublished - 5 Aug 2019

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