Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress

Karita Peltonen, Laureen Colis, Hester Liu, Sari Jäämaa, Zhewei Zhang, Taija Af Hällström, Henna M. Moore, Paul Sirajuddin, Marikki Laiho

Research output: Contribution to journalArticle

Abstract

Activation of the p53 pathway has been considered a therapeutic strategy to target cancers. We have previously identified several p53-activating small molecules in a cell-based screen. Two of the compounds activated p53 by causing DNA damage, but this modality was absent in the other four. We recently showed that one of these, BMH-21, inhibits RNA polymerase I (Pol I) transcription, causes the degradation of Pol I catalytic subunit RPA194, and has potent anticancer activity. We show here that three remaining compounds in this screen, BMH-9, BMH-22, and BMH-23, cause reorganization of nucleolar marker proteins consistent with segregation of the nucleolus, a hallmark of Pol I transcription stress. Further, the compounds destabilize RPA194 in a proteasome-dependent manner and inhibit nascent rRNA synthesis and expression of the 45S rRNA precursor. BMH-9- and BMH-22-mediated nucleolar stress was detected in ex vivo-cultured human prostate tissues indicating good tissue bioactivity. Testing of closely related analogues showed that their activities were chemically constrained. Viability screen for BMH-9, BMH-22, and BMH-23 in the NCI60 cancer cell lines showed potent anticancer activity across many tumor types. Finally, we show that the Pol I transcription stress by BMH-9, BMH-22, and BMH-23 is independent of p53 function. These results highlight the dominant impact of Pol I transcription stress on p53 pathway activation and bring forward chemically novel lead molecules for Pol I inhibition, and, potentially, cancer targeting.

Original languageEnglish (US)
Pages (from-to)2537-2546
Number of pages10
JournalMolecular cancer therapeutics
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Peltonen, K., Colis, L., Liu, H., Jäämaa, S., Zhang, Z., Hällström, T. A., Moore, H. M., Sirajuddin, P., & Laiho, M. (2014). Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress. Molecular cancer therapeutics, 13(11), 2537-2546. https://doi.org/10.1158/1535-7163.MCT-14-0256