The Cytotoxic Natural Product Vioprolide A Targets Nucleolar Protein 14, Which Is Essential for Ribosome Biogenesis

Volker C. Kirsch, Christina Orgler, Simone Braig, Irmela Jeremias, David Auerbach, Rolf Müller, Angelika M. Vollmar, Stephan A. Sieber

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Novel targets are needed for treatment of devastating diseases such as cancer. For decades, natural products have guided innovative therapies by addressing diverse pathways. Inspired by the potent cytotoxic bioactivity of myxobacterial vioprolides A–D, we performed in-depth studies on their mode of action. Based on its prominent potency against human acute lymphoblastic leukemia (ALL) cells, we conducted thermal proteome profiling (TPP) and deciphered the target proteins of the most active derivative vioprolide A (VioA) in Jurkat cells. Nucleolar protein 14 (NOP14), which is essential in ribosome biogenesis, was confirmed as a specific target of VioA by a suite of proteomic and biological follow-up experiments. Given its activity against ALL cells compared to healthy lymphocytes, VioA exhibits unique therapeutic potential for anticancer therapy through a novel mode of action.

Original languageEnglish
Pages (from-to)1595-1600
Number of pages6
JournalAngewandte Chemie International Edition in English
Volume59
Issue number4
DOIs
StatePublished - 20 Jan 2020

Keywords

  • acute lymphoblastic leukemia
  • natural products
  • quantitative proteomics
  • ribosomess
  • target identification

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