Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression

Qingxiang Lin, Yuan He, Xue Wang, Yong Zhang, Meichun Hu, Weikai Guo, Yundong He, Tao Zhang, Li Lai, Zhenliang Sun, Zhengfang Yi, Mingyao Liu, Yihua Chen

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Rapid metabolism differentiates cancer cells from normal cells and relies on anaplerotic pathways. However, the mechanisms of anaplerosis-associated enzymes are rarely understood. The lack of potent and selective antimetabolism drugs restrains further clinical investigations. A small molecule ZY-444 ((N4-((5-(4-(benzyloxy)phenyl)-2-thiophenyl)methyl)-N2-isobutyl-2,4-pyrimidinediamine) is discovered to inhibit cancer cell proliferation specifically, having potent efficacies against tumor growth, metastasis, and recurrence. ZY-444 binds to cellular pyruvate carboxylase (PC), a key anaplerotic enzyme of the tricarboxylic acid cycle, and inactivates its catalytic activity. PC inhibition suppresses breast cancer growth and metastasis through inhibiting the Wnt/β-catenin/Snail signaling pathway. Lower PC expression in patient tumors is correlated with significant survival benefits. Comparative profiles of PC expression in cancer versus normal tissues implicate the tumor selectivity of ZY-444. Overall, ZY-444 holds promise therapeutically as an anti-cancer metabolism agent.

Original languageEnglish (US)
Article number1903483
JournalAdvanced Science
Volume7
Issue number9
DOIs
StatePublished - May 1 2020

Keywords

  • breast cancer
  • cancer metabolism
  • pyruvate carboxylase
  • small molecule ZY-444
  • Wnt/β-catenin/Snail pathway

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Chemical Engineering(all)
  • Materials Science(all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Engineering(all)
  • Physics and Astronomy(all)

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