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Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress.
Mol Cancer Ther 2014; 13(11):2537-46MC

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.

Authors+Show Affiliations

Center for Drug Research, University of Helsinki, Helsinki, Finland.Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.Center for Drug Research, University of Helsinki, Helsinki, Finland.Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.Center for Drug Research, University of Helsinki, Helsinki, Finland.Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.Center for Drug Research, University of Helsinki, Helsinki, Finland. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. mlaiho1@jhmi.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25277384

Citation

Peltonen, Karita, et al. "Small Molecule BMH-compounds That Inhibit RNA Polymerase I and Cause Nucleolar Stress." Molecular Cancer Therapeutics, vol. 13, no. 11, 2014, pp. 2537-46.
Peltonen K, Colis L, Liu H, et al. Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress. Mol Cancer Ther. 2014;13(11):2537-46.
Peltonen, K., Colis, L., Liu, H., Jäämaa, S., Zhang, Z., Af Hällström, T., ... Laiho, M. (2014). Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress. Molecular Cancer Therapeutics, 13(11), pp. 2537-46. doi:10.1158/1535-7163.MCT-14-0256.
Peltonen K, et al. Small Molecule BMH-compounds That Inhibit RNA Polymerase I and Cause Nucleolar Stress. Mol Cancer Ther. 2014;13(11):2537-46. PubMed PMID: 25277384.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress. AU - Peltonen,Karita, AU - Colis,Laureen, AU - Liu,Hester, AU - Jäämaa,Sari, AU - Zhang,Zhewei, AU - Af Hällström,Taija, AU - Moore,Henna M, AU - Sirajuddin,Paul, AU - Laiho,Marikki, Y1 - 2014/10/02/ PY - 2014/10/4/entrez PY - 2014/10/4/pubmed PY - 2015/11/11/medline SP - 2537 EP - 46 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 13 IS - 11 N2 - 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. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/25277384/Small_molecule_BMH_compounds_that_inhibit_RNA_polymerase_I_and_cause_nucleolar_stress_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=25277384 DB - PRIME DP - Unbound Medicine ER -