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

doi:10.1158/1535-7163.mct-14-0256

Cited by 77 publications

(72 citation statements)

References 38 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We hypothesize this stalling of RNAP2 promotes ubiquitination and degradation of RPB1, ultimately interfering with RNA synthesis, which may contribute to efficacy against treatment refractory CaP. Other molecules that interfere with RNA synthesis are proposed as potential drug candidates for CaP (13,20). …”

Section: Discussionmentioning

confidence: 99%

A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer

et al. 2017

View full text Add to dashboard Cite

The LREX’ prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor (NHR), glucocorticoid receptor (GR), which has similar DNA binding specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein-DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand binding domain antagonists are ineffective. We reported previously that a pyrrole-imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX’ cells, Py-Im polyamide interfered with both androgen receptor- and glucocorticoid receptor-driven gene expression, while enzalutamide interfered with only that of androgen receptor. Genomic analyses indicated immediate interference with the androgen receptor transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Interestingly, another inhibitor of RNA Pol I has been developed, BMH-21. This molecule binds preferentially to rRNA-encoding DNA, and reportedly behaves in a TP53-independent manner 16 . Further studies are required to determine if this molecule also has preferential activity against chemoresistant populations.…”

Section: Discussionmentioning

confidence: 99%

“…However, none of these drugs directly target Pol I 10–12 . Recently, small molecule inhibitors have been developed, such as CX-5461 and CX-3543, which have apparent specificity for RNA Pol I 13–16 . CX-5461 does not inhibit mRNA synthesis by RNA polymerase II, does not inhibit DNA replication or protein synthesis, and has preferential activity for cancer cells over non-transformed cells 13 .…”

Section: Introductionmentioning

confidence: 99%

Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer

Cornelison

Dobbin

Katre

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose A hallmark of neoplasia is increased ribosome biogenesis, and targeting this process with RNA polymerase I (Pol I) inhibitors has shown some efficacy. We examined the contribution and potential targeting of ribosomal machinery in chemotherapy resistant and sensitive models of ovarian cancer. Experimental Design Pol I machinery expression was examined, and subsequently targeted with the Pol I inhibitor CX-5461, in ovarian cancer cell lines, an immortalized surface epithelial line, and patient derived xenograft (PDX) models with and without chemotherapy. Effects on viability, Pol I occupancy of rDNA, ribosomal content, and chemosensitivity were examined. Results In PDX models, ribosomal machinery components were increased in chemotherapy-treated tumors compared to controls. 13 cell lines were sensitive to CX-5461, with IC50s 25nM – 2μM. Interestingly two chemoresistant lines were 10.5- and 5.5-fold more sensitive than parental lines. CX-5461 induced DNA damage checkpoint activation and G2/M arrest with increased γH2AX staining. Chemoresistant cells had 2-4-fold increased rDNA Pol I occupancy and increased rRNA synthesis, despite having slower proliferation rates, while ribosome abundance and translational efficiency were not impaired. In five PDX models treated with CX-5461, one showed a complete response, one a 55% reduction in tumor volume, and one maintained stable disease for 45 days. Conclusions Pol I inhibition with CX-5461 shows high activity in ovarian cancer cell lines and PDX models, with an enhanced effect on chemoresistant cells. Effects occur independent of proliferation rates or dormancy. This represents a novel therapeutic approach that may have preferential activity in chemoresistant populations.

show abstract

“…Morphological changes in the nucleoli, the sites of Pol I transcription and ribosome subunit assembly, have been associated with poor cancer prognosis for over 100 years (18). We and others have demonstrated targeting Pol I transcription as a novel approach for cancer treatment (19)(20)(21)(22). Inhibition of Pol I transcription using the specific small-molecule inhibitor CX-5461 can selectivity kill cancer cells in vivo (19,20,23).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

Sanij

Hannan

Yan

et al. 2019

Preprint

View full text Add to dashboard Cite

High-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

show abstract

Small Molecule BMH-Compounds That Inhibit RNA Polymerase I and Cause Nucleolar Stress

Cited by 77 publications

References 38 publications

A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer

A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer

Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer

Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

Contact Info

Product

Resources

About