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

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RNA Polymerase I
Neoplasms
RNA Precursors
Proteasome Endopeptidase Complex
Nuclear Proteins
DNA Damage
Prostate
Catalytic Domain
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress. / Peltonen, Karita; Colis, Laureen; Liu, Hester; Jäämaa, Sari; Zhang, Zhewei; Hällström, Taija Af; Moore, Henna M.; Sirajuddin, Paul; Laiho, Marikki.

In: Molecular Cancer Therapeutics, Vol. 13, No. 11, 01.11.2014, p. 2537-2546.

Research output: Contribution to journalArticle

Peltonen, K, Colis, L, Liu, H, Jäämaa, S, Zhang, Z, Hällström, TA, Moore, HM, Sirajuddin, P & Laiho, M 2014, 'Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress', Molecular Cancer Therapeutics, vol. 13, no. 11, pp. 2537-2546. https://doi.org/10.1158/1535-7163.MCT-14-0256
Peltonen, Karita ; Colis, Laureen ; Liu, Hester ; Jäämaa, Sari ; Zhang, Zhewei ; Hällström, Taija Af ; Moore, Henna M. ; Sirajuddin, Paul ; Laiho, Marikki. / Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 11. pp. 2537-2546.
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