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 journalArticle

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
Number of pages6
JournalANGEWANDTE CHEMIE-INTERNATIONAL EDITION
DOIs
Publication statusE-pub ahead of print - 28 Jun 2019

Cite this

Hu, Di ; Yang, Chen ; Lok, Chun-Nam ; Xing, Fangrong ; Lee, Pui-Yan ; Fung, Yi Man Eva ; Jiang, Haibo ; Che, Chi-Ming. / An Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target. In: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION. 2019.
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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.",
keywords = "antitumor agents, asparagine synthetase, N-heterocyclic carbenes, platinum complexes, thermal proteome profiling, HETEROCYCLIC CARBENE COMPLEXES, CELL-PROLIFERATION, RATIONAL DESIGN, CANCER-CELLS, PLATINUM, CISPLATIN, CHEMOTHERAPY, LIGANDS, ADAPTATION, MICROSCOPY",
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An Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target. / Hu, Di; Yang, Chen; Lok, Chun-Nam; Xing, Fangrong; Lee, Pui-Yan; Fung, Yi Man Eva; Jiang, Haibo; Che, Chi-Ming.

In: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 28.06.2019.

Research output: Contribution to journalArticle

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T1 - An Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target

AU - Hu, Di

AU - Yang, Chen

AU - Lok, Chun-Nam

AU - Xing, Fangrong

AU - Lee, Pui-Yan

AU - Fung, Yi Man Eva

AU - Jiang, Haibo

AU - Che, Chi-Ming

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AB - 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.

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KW - platinum complexes

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KW - HETEROCYCLIC CARBENE COMPLEXES

KW - CELL-PROLIFERATION

KW - RATIONAL DESIGN

KW - CANCER-CELLS

KW - PLATINUM

KW - CISPLATIN

KW - CHEMOTHERAPY

KW - LIGANDS

KW - ADAPTATION

KW - MICROSCOPY

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