TY - JOUR
T1 - The Cytotoxic Natural Product Vioprolide A Targets Nucleolar Protein 14, Which Is Essential for Ribosome Biogenesis
AU - Kirsch, Volker C.
AU - Orgler, Christina
AU - Braig, Simone
AU - Jeremias, Irmela
AU - Auerbach, David
AU - Müller, Rolf
AU - Vollmar, Angelika M.
AU - Sieber, Stephan A.
N1 - Publisher Copyright:
© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
PY - 2020/1/20
Y1 - 2020/1/20
N2 - 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.
AB - 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.
KW - acute lymphoblastic leukemia
KW - natural products
KW - quantitative proteomics
KW - ribosomess
KW - target identification
UR - http://www.scopus.com/inward/record.url?scp=85076400631&partnerID=8YFLogxK
U2 - 10.1002/anie.201911158
DO - 10.1002/anie.201911158
M3 - Article
C2 - 31658409
AN - SCOPUS:85076400631
SN - 1433-7851
VL - 59
SP - 1595
EP - 1600
JO - Angewandte Chemie International Edition in English
JF - Angewandte Chemie International Edition in English
IS - 4
ER -