title: Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress.
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.affiliation: Center for Drug Research, University of Helsinki, Helsinki, Finland.
authors.forename: Karita
authors.initials: K
authors.lastname: Peltonen
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Laureen
authors.initials: L
authors.lastname: Colis
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Hester
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center for Drug Research, University of Helsinki, Helsinki, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Jäämaa
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Zhewei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: Taija
authors.initials: T
authors.lastname: Af Hällström
authors.affiliation: Center for Drug Research, University of Helsinki, Helsinki, Finland.
authors.forename: Henna M
authors.initials: HM
authors.lastname: Moore
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Paul
authors.initials: P
authors.lastname: Sirajuddin
authors.affiliation: 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.
authors.forename: Marikki
authors.initials: M
authors.lastname: Laiho
mesh_terms: D001859:Bone Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D012516:Osteosarcoma / Q000188:drug therapy; D011467:Prostate / Q000187:drug effects; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D012318:RNA Polymerase I