Small molecule inhibitor of Igf2bp1 represses Kras and a pro-oncogenic phenotype in cancer cells

Nadav Wallis, Froma Oberman, Khriesto Shurrush, Nicolas Germain, Gila Greenwald, Tehila Gershon, Talia Pearl, Giancarlo Abis, Vikash Singh, Amandeep Singh, Arun K. Sharma, Haim M. Barr, Andres Ramos, Vladimir S. Spiegelman, Joel K. Yisraeli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).

Original languageAmerican English
Pages (from-to)26-43
Number of pages18
JournalRNA Biology
Volume19
Issue number1
DOIs
StatePublished - 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • Fluorescence polarization
  • Igf2bps
  • Kras inhibitor
  • RNA binding proteins

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