Article
Multidisciplinary Sciences
Stacey L. Lehman, Kayla R. Schwartz, Shrankhla Maheshwari, Kevin Camphausen, Philip J. Tofilon
Summary: Inhibitors of ribosome biogenesis can increase the sensitivity of cancer cells to radiotherapy. This study tested the radiosensitizing potential of the small molecule RNA polymerase I inhibitor CX-5461 and found that it enhanced the effectiveness of radiation therapy in tumor cells through the mechanism of mitotic catastrophe.
SCIENTIFIC REPORTS
(2022)
Article
Oncology
Mitchell G. Lawrence, Laura H. Porter, Nicholas Choo, David Pook, Jeremy P. Grummet, Carmel J. Pezaro, Shahneen Sandhu, Susanne Ramm, Jennii Luu, Andrew Bakshi, David L. Goode, Elaine Sanij, Richard B. Pearson, Ross D. Hannan, Kaylene J. Simpson, Renea A. Taylor, Gail P. Risbridger, Luc Furic
Summary: Combination therapy with CX-5461 and talazoparib is effective for HR-proficient CRPC tumors that are not suitable for monotherapy with PARP inhibitors, significantly reducing tumor growth and increasing DNA damage levels in patient-derived xenografts.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Multidisciplinary Sciences
Min Pan, William C. Wright, Richard H. Chapple, Asif Zubair, Manbir Sandhu, Jake E. Batchelder, Brandt C. Huddle, Jonathan Low, Kaley B. Blankenship, Yingzhe Wang, Brittney Gordon, Payton Archer, Samuel W. Brady, Sivaraman Natarajan, Matthew J. Posgai, John Schuetz, Darcie Miller, Ravi Kalathur, Siquan Chen, Jon Patrick Connelly, M. Madan Babu, Michael A. Dyer, Shondra M. Pruett-Miller, Burgess B. Freeman, Taosheng Chen, Lucy A. Godley, Scott C. Blanchard, Elizabeth Stewart, John Easton, Paul Geeleher
Summary: The study found that the small molecule CX-5461 has selective cytotoxicity in high-risk neuroblastoma and synergizes with topoisomerase I inhibitors to improve survival. However, it was discovered that the primary target of CX-5461 in this disease is topoisomerase II beta, not RNA-POL I, raising unexpected safety concerns.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Chang-Won Kang, Katherine M. Hannan, Anneke C. Blackburn, Amos H. P. Loh, Kuick Chik Hong, Goh Jian Yuan, Nadine Hein, Denis Drygin, Ross D. Hannan, Lucy A. Coupland
Summary: This study confirmed SK-UT-1 as a representative model for uterine leiomyosarcoma and demonstrated the significant potential of CX-5461 as a novel adjuvant for this rare cancer.
INVESTIGATIONAL NEW DRUGS
(2022)
Article
Dermatology
Xiao Wu, Qihui Yin, Jie Wang, Chaochao Dai, Jianli Wang, Xiaosun Guo, Fan Jiang
Summary: CX-5461, a selective inhibitor of RNA polymerase I, demonstrates therapeutic effects on experimental psoriasis in mice, possibly through multiple mechanisms including anti-proliferative, anti-inflammatory, and anti-angiogenic activities.
EXPERIMENTAL DERMATOLOGY
(2023)
Review
Oncology
Stephanie Pitts, Marikki Laiho
Summary: Building of ribosomes is a massive and energy-consuming process, which is heavily relied upon by cancer cells. RNA polymerase I, critical in ribosome biogenesis, is deregulated in cancer cells, providing a potential target for cancer therapy. This article reviews the regulation of Pol I transcription and the development of targeted agents against this process.
Article
Multidisciplinary Sciences
Luc Snyers, Sylvia Laffer, Renate Loehnert, Klara Weipoltshammer, Christian Schoefer
Summary: In this study, the researchers investigated the impact of the compound CX-5461 on nucleolar morphology and function. The results showed that exposure to CX-5461 caused significant changes in nucleolar shape, with nucleoli becoming compact and spherical. The researchers also observed increased amounts of DNA damage response indicators and DNA unwinding enzymes in the nucleoli. Furthermore, incubation with CX-5461 led to increased senescence and decreased cell replication.
SCIENTIFIC REPORTS
(2022)
Review
Genetics & Heredity
Rachel McNamar, Katrina Rothblum, Lawrence Rothblum
Summary: Pol I is responsible for transcribing ribosomal DNA genes in eukaryotes, and abnormalities in its activity are linked to cancer and genetic diseases. Studies show differences in Pol I transcription between yeast and mammals, which may affect the function and regulation of PAFs.
Article
Pharmacology & Pharmacy
Xia Xu, Hua Feng, Chaochao Dai, Weida Lu, Jun Zhang, Xiaosun Guo, Qihui Yin, Jianli Wang, Xiaopei Cui, Fan Jiang
Summary: The study showed that CX-5461 had good tolerance for in vivo treatments in rats with PAH, preventing pulmonary arterial remodelling, perivascular inflammation, and pulmonary hypertension, leading to improved survival. In vivo and in vitro experiments demonstrated that CX-5461 induced cell cycle arrest in human pulmonary arterial smooth muscle cells through increased activation of p53, suggesting that pharmacological inhibition of Pol I could be a novel therapeutic strategy for drug-resistant PAH.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Oncology
Robert Cornelison, Kuntal Biswas, Danielle C. Llaneza, Alexandra R. Harris, Nisha G. Sosale, Matthew J. Lazzara, Charles N. Landen
Summary: Treatment with CX-5461 leads to the accumulation of cytosolic dsDNA, activating the cGAS-STING-TBK1-IRF3 innate immune pathway and inducing type I interferon production. This immune activation may be a powerful mechanism of action to exploit in novel drug combinations for increasing immunotherapy efficacy and potentially limiting deleterious toxicities with some cancer specificity.
Article
Biochemistry & Molecular Biology
Hyo-Gun Kim, Joshua R. Huot, Fabrizio Pin, Bin Guo, Andrea Bonetto, Gustavo A. Nader
Summary: Muscle wasting in cancer, particularly in the context of ovarian cancer, is associated with reduced ribosomal capacity and impaired rDNA transcription, leading to compromised protein synthesis and anabolic deficits.
Article
Chemistry, Inorganic & Nuclear
Zhen-Lei Zhang, Rui Rong, Xuan-Lin Ren, Ling-Wen Xu, Wen-Jing Lian, Xin Qiao, Jing-Yuan Xu
Summary: Unrestricted cell growth and proliferation of cancer cells correlate with accelerated RNA polymerase I transcription and upregulation of ribosome biogenesis. CX-5461, a Pol I selective inhibitor with multitargeting property and synthetic lethality in HR-deficient cancers, was used to modify cisplatin to obtain two monofunctional platinum Pol I selective inhibitors. The study demonstrated that P1-Q1 and P1-Q2 could specifically target Pol I transcription machinery and overcome platinum drug resistance in BRCA1-deficient A549 cells.
INORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Multidisciplinary Sciences
Karla T. Falcon, Kristin E. N. Watt, Soma Dash, Ruonan Zhao, Daisuke Sakai, Emma L. Moore, Sharien Fitriasari, Melissa Childers, Mihaela E. Sardiu, Selene Swanson, Dai Tsuchiya, Jay Unruh, George Bugarinovic, Lin Li, Rita Shiang, Annita Achilleos, Jill Dixon, Michael J. Dixon, Paul A. Trainor
Summary: This study investigates the importance of ribosomal RNA (rRNA) transcription in craniofacial development and the implications of disruptions in this process. The researchers discovered that high expression of Pol I subunits in neuroepithelium and neural crest cells (NCCs) sustains elevated rRNA transcription, supporting the high levels of protein translation in these cells. However, disruptions in rRNA synthesis in NCCs can lead to p53 protein accumulation, NCC apoptosis, and craniofacial anomalies. Compound mutations in Pol I subunits further exacerbate these anomalies. Mechanistically, diminished rRNA synthesis causes an imbalance between rRNA and ribosomal proteins, affecting the binding of these proteins with Mdm2 and p53. This study highlights the critical role of rRNA transcription in craniofacial development and its specific sensitivities to disruptions in certain congenital craniofacial disorders.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Genetics & Heredity
Abigail K. Huffines, Yvonne J. K. Edwards, David A. Schneider
Summary: The RNA polymerase (Pol) I transcription defect caused by the deletion of Spt4 protein may affect the transcription elongation process. The complex formed by Spt4 and Spt5 promotes Pol I processivity, enhancing transcription elongation through G-rich regions of ribosomal DNA.
Article
Biochemistry & Molecular Biology
Pallavi Mohapatra, Sibasish Mohanty, Shamima Azma Ansari, Omprakash Shriwas, Arup Ghosh, Rachna Rath, Saroj Kumar Das Majumdar, Rajeeb K. Swain, Sunil K. Raghav, Rupesh Dash
Summary: CMTM6 is a major driver of cisplatin resistance in oral squamous cell carcinomas. The study explores the detailed mechanism of how CMTM6 rewires cisplatin resistance by regulating the ribosome biogenesis network.
Article
Oncology
Jixuan Gao, MoonSun Jung, Chelsea Mayoh, Pooja Venkat, Katherine M. Hannan, Jamie Fletcher, Alvin Kamili, Andrew J. Gifford, Eric P. Kusnadi, Richard B. Pearson, Ross D. Hannan, Michelle Haber, Murray D. Norris, Klaartje Somers, Michelle J. Henderson
Article
Biology
Chue Vin Chin, Jisha Antony, Sarada Ketharnathan, Anastasia Labudina, Gregory Gimenez, Kate M. Parsons, Jinshu He, Amee J. George, Maria Michela Pallotta, Antonio Musio, Antony Braithwaite, Parry Guilford, Ross D. Hannan, Julia A. Horsfield
Review
Genetics & Heredity
Konstantin I. Panov, Katherine Hannan, Ross D. Hannan, Nadine Hein
Summary: Nucleoli form around actively transcribed ribosomal RNA genes, and their morphology and size change with the transcription status of RNA Polymerase I. The number of rDNA repeats and the proportion of actively transcribed rRNA genes vary between cell types, individuals, and disease states.
Article
Oncology
Mitchell G. Lawrence, Laura H. Porter, Nicholas Choo, David Pook, Jeremy P. Grummet, Carmel J. Pezaro, Shahneen Sandhu, Susanne Ramm, Jennii Luu, Andrew Bakshi, David L. Goode, Elaine Sanij, Richard B. Pearson, Ross D. Hannan, Kaylene J. Simpson, Renea A. Taylor, Gail P. Risbridger, Luc Furic
Summary: Combination therapy with CX-5461 and talazoparib is effective for HR-proficient CRPC tumors that are not suitable for monotherapy with PARP inhibitors, significantly reducing tumor growth and increasing DNA damage levels in patient-derived xenografts.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Oncology
Chang-Won Kang, Katherine M. Hannan, Anneke C. Blackburn, Amos H. P. Loh, Kuick Chik Hong, Goh Jian Yuan, Nadine Hein, Denis Drygin, Ross D. Hannan, Lucy A. Coupland
Summary: This study confirmed SK-UT-1 as a representative model for uterine leiomyosarcoma and demonstrated the significant potential of CX-5461 as a novel adjuvant for this rare cancer.
INVESTIGATIONAL NEW DRUGS
(2022)
Article
Biotechnology & Applied Microbiology
Diksha Sharma, Sylvie Hermann-Le Denmat, Nicholas J. Matzke, Katherine Hannan, Ross D. Hannan, Justin M. O'Sullivan, Austen R. D. Ganley
Summary: The article presents a new method for estimating rDNA copy number based on modal coverage, overcoming limitations of existing methods. The study shows significant variation in copy number both within and between populations.
Article
Cell Biology
Katherine M. Hannan, Priscilla Soo, Mei S. Wong, Justine K. Lee, Nadine Hein, Perlita Poh, Kira D. Wysoke, Tobias D. Williams, Christian Montellese, Lorey K. Smith, Sheren J. Al-Obaidi, Lorena Nunez-Villacis, Megan Pavy, Jin-Shu He, Kate M. Parsons, Karagh E. Loring, Tess Morrison, Jeannine Diesch, Gaetan Burgio, Rita Ferreira, Zhi-Ping Feng, Cathryn M. Gould, Piyush B. Madhamshettiwar, Johan Flygare, Thomas J. Gonda, Kaylene J. Simpson, Ulrike Kutay, Richard B. Pearson, Christoph Engel, Nicholas J. Watkins, Ross D. Hannan, Amee J. George
Summary: The nucleolar surveillance pathway monitors nucleolar integrity and responds to nucleolar stress by mediating binding of ribosomal proteins to MDM2, resulting in p53 accumulation. The ribosome biogenesis axis is identified as the most potent class of genes whose disruption stabilizes p53. Genes critical for regulation of this pathway, including HEATR3, are identified. The nucleolar surveillance pathway is essential for the ability of all nuclear-acting stresses, including DNA damage, to induce p53 accumulation, indicating its central role in regulating nuclear p53 abundance in response to various stresses.
Article
Pharmacology & Pharmacy
Gregory Gauthier-Coles, Angelika Broer, Malcolm Donald McLeod, Amee J. George, Ross D. Hannan, Stefan Broer
Summary: SNAT2 is an important amino acid transporter involved in amino acid accumulation, cellular osmolarity, and cell growth. A potent inhibitor of SNAT2 has been identified through high-throughput screening, with selectivity against other transporters. Combined with a glucose transport inhibitor, this compound can halt the proliferative growth of cancer cells.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Developmental Biology
Olga Zaytseva, Naomi C. Mitchell, Damien Muckle, Caroline Delandre, Zuqin Nie, Janis K. Werner, John T. Lis, Eduardo Eyras, Ross D. Hannan, David L. Levens, Owen J. Marshall, Leonie M. Quinn
Summary: FUBP1 and Psi, members of the FUSE Binding Protein family, regulate gene transcription by binding to single-stranded DNA and RNA, promoting cell growth and division. Psi activates Myc and stg to promote cell proliferation, while repressing the transcription of tok, a growth inhibitor.
Article
Biology
Anne Steins, Christina Carroll, Fui Jiun Choong, Amee J. George, Jin-Shu He, Kate M. Parsons, Shouya Feng, Si Ming Man, Cathelijne Kam, Lex M. van Loon, Perlita Poh, Rita Ferreira, Graham J. Mann, Russell L. Gruen, Katherine M. Hannan, Ross Hannan, Klaus-Martin Schulte
Summary: The safety of Povidone-iodine (PVP-I) is controversial, and its toxicity is mainly caused by diatomic iodine (I2). The higher the concentration and duration of PVP-I, the greater the toxicity to cells. Additionally, PVP-I can disrupt cell membranes and lipid rafts, leading to cellular dysfunction. Therefore, a reevaluation of PVP-I in clinical practice is necessary to avoid unnecessary toxicity.
LIFE SCIENCE ALLIANCE
(2023)
Article
Chemistry, Multidisciplinary
Madushani Amarasiri, Yen Vo, Michael G. Gardiner, Perlita Poh, Priscilla Soo, Megan Pavy, Nadine Hein, Rita Ferreira, Katherine M. Hannan, Ross D. Hannan, Martin G. Banwell
Summary: Regio-isomeric alkynyl-substituted derivatives of the RNA Polymerase I transcription inhibitor CX-5461 were prepared and subjected to click reactions with certain alkyl azides. Among the tested compounds, only alkyne 3 remained active in a human acute myeloid leukemia cell line model, but with lower potency than parent compound 1.
AUSTRALIAN JOURNAL OF CHEMISTRY
(2021)
Review
Chemistry, Multidisciplinary
Stephanie J. Franks, Kate Firipis, Rita Ferreira, Katherine M. Hannan, Richard J. Williams, Ross D. Hannan, David R. Nisbet
MATERIALS HORIZONS
(2020)