Abstract DDT02-04: A novel PRMT5 inhibitor with potent in vitro and in vivo activity in preclinical lung cancer models
| Autor: | Dushen Chetty, Matthew V. Lorenzi, Sylvie Laquerre, Gaston Stanislas Marcella Diels, Edward C. Lawson, Carol Yanovich, Italo Poggesi, Ivan Somers, Dana Gaffney, Wim Bert Griet Schepens, Hillary Millar, Weimei Sun, Tongfei Wu, Lijs Beke, Viellevoye Marcel, Marc Du Jardin, Petra Vinken, Erika van Heerde, Tinne Verhulst, James P. Edwards, Dirk Brehmer, Barbara Herkert, Geert Mannens, Vineet Pande, Alain Philippe Poncelet, Christopher Moy, An Boeckx, Marc Parade, Thomas Nys, Jan-Willem Thuring, Lieven Meerpoel, Joannes T. M. Linders |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Methyltransferase business.industry Protein arginine methyltransferase 5 Methylation medicine.disease_cause medicine.disease In vitro 03 medical and health sciences 030104 developmental biology Oncology In vivo Cancer research medicine Cytotoxic T cell Carcinogenesis business Lung cancer |
| Zdroj: | Cancer Research. 77:DDT02-04 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | PRMT5 is a type II methyltransferase that specifically adds methyl groups to arginine as a long-lasting post-translational modification. The PRMT5/MEP50 complex regulates a plethora of cellular processes, such as epigenetics and splicing, which are notable events involved in tumorigenesis. Although not frequently mutated or amplified in tumors, elevated PRMT5 protein levels in lung and hematologic cancers are correlated with poorer survival. The PRMT5 inhibitor JNJ-64619178 has been selected as a clinical candidate based on its high selectivity and potency (subnanomolar range) under different in vitro and cellular conditions, paired with favorable pharmacokinetics and safety properties. JNJ-64619178 binds into the SAM binding pocket and reaches the substrate binding pocket to inhibit PRMT5/MEP50 function in a time-dependent manner. Broad cell line panel profiling of JNJ-64619178 revealed a wide range of sensitivity, which is indicative of a genomic dependency instead of a general cytotoxic on-target consequence of PRMT5 inhibition. Further investigations indicate a synthetic lethal correlation between PRMT5 inhibition and key cancer driver pathways. JNJ-64619178, dosed orally (10 mg/kg, every day), showed selective and efficient blockage of the methylation of SMD1/3 proteins, which are crucial components of the spliceosome and substrates of PRMT5/MEP50. JNJ-64619178 also demonstrated tumor regression in a biomarker-driven human small cell lung cancer xenograft model (NCI-H1048) and prolonged tumor growth inhibition after dosing cessation. In rodent and nonrodent toxicology studies, a tolerated dose of JNJ-64619178 has been identified, with the observed toxicity consistent with on-target activity. In summary, JNJ-64619178 has a favorable preclinical package that supports clinical testing in patients diagnosed with lung cancer and hematologic malignancies. Citation Format: Dirk Brehmer, Tongfei Wu, Geert Mannens, Lijs Beke, Petra Vinken, Dana Gaffney, Weimei Sun, Vineet Pande, Jan-Willem Thuring, Hillary Millar, Italo Poggesi, Ivan Somers, An Boeckx, Marc Parade, Erika van Heerde, Thomas Nys, Carol Yanovich, Barbara Herkert, Tinne Verhulst, Marc Du Jardin, Lieven Meerpoel, Christopher Moy, Gaston Diels, Marcel Viellevoye, Wim Schepens, Alain Poncelet, Joannes T. Linders, Edward C. Lawson, James P. Edwards, Dushen Chetty, Sylvie Laquerre, Matthew V. Lorenzi. A novel PRMT5 inhibitor with potent in vitro and in vivo activity in preclinical lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT02-04. doi:10.1158/1538-7445.AM2017-DDT02-04 |
| Databáze: | OpenAIRE |
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