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Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity
The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for Cancer Research
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9398174/ https://www.ncbi.nlm.nih.gov/pubmed/34583982 http://dx.doi.org/10.1158/1535-7163.MCT-21-0367 |
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author | Brehmer, Dirk Beke, Lijs Wu, Tongfei Millar, Hillary J. Moy, Christopher Sun, Weimei Mannens, Geert Pande, Vineet Boeckx, An van Heerde, Erika Nys, Thomas Gustin, Emmanuel M. Verbist, Bie Zhou, Longen Fan, Yue Bhargava, Vipul Safabakhsh, Pegah Vinken, Petra Verhulst, Tinne Gilbert, Angelique Rai, Sumit Graubert, Timothy A. Pastore, Friederike Fiore, Danilo Gu, Junchen Johnson, Amy Philippar, Ulrike Morschhäuser, Barbara Walker, David De Lange, Desiree Keersmaekers, Vikki Viellevoye, Marcel Diels, Gaston Schepens, Wim Thuring, Jan Willem Meerpoel, Lieven Packman, Kathryn Lorenzi, Matthew V. Laquerre, Sylvie |
author_facet | Brehmer, Dirk Beke, Lijs Wu, Tongfei Millar, Hillary J. Moy, Christopher Sun, Weimei Mannens, Geert Pande, Vineet Boeckx, An van Heerde, Erika Nys, Thomas Gustin, Emmanuel M. Verbist, Bie Zhou, Longen Fan, Yue Bhargava, Vipul Safabakhsh, Pegah Vinken, Petra Verhulst, Tinne Gilbert, Angelique Rai, Sumit Graubert, Timothy A. Pastore, Friederike Fiore, Danilo Gu, Junchen Johnson, Amy Philippar, Ulrike Morschhäuser, Barbara Walker, David De Lange, Desiree Keersmaekers, Vikki Viellevoye, Marcel Diels, Gaston Schepens, Wim Thuring, Jan Willem Meerpoel, Lieven Packman, Kathryn Lorenzi, Matthew V. Laquerre, Sylvie |
author_sort | Brehmer, Dirk |
collection | PubMed |
description | The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo, with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity–driven tumors. |
format | Online Article Text |
id | pubmed-9398174 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-93981742023-01-05 Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity Brehmer, Dirk Beke, Lijs Wu, Tongfei Millar, Hillary J. Moy, Christopher Sun, Weimei Mannens, Geert Pande, Vineet Boeckx, An van Heerde, Erika Nys, Thomas Gustin, Emmanuel M. Verbist, Bie Zhou, Longen Fan, Yue Bhargava, Vipul Safabakhsh, Pegah Vinken, Petra Verhulst, Tinne Gilbert, Angelique Rai, Sumit Graubert, Timothy A. Pastore, Friederike Fiore, Danilo Gu, Junchen Johnson, Amy Philippar, Ulrike Morschhäuser, Barbara Walker, David De Lange, Desiree Keersmaekers, Vikki Viellevoye, Marcel Diels, Gaston Schepens, Wim Thuring, Jan Willem Meerpoel, Lieven Packman, Kathryn Lorenzi, Matthew V. Laquerre, Sylvie Mol Cancer Ther MCT First Disclosures The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo, with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity–driven tumors. American Association for Cancer Research 2021-12-01 2021-09-28 /pmc/articles/PMC9398174/ /pubmed/34583982 http://dx.doi.org/10.1158/1535-7163.MCT-21-0367 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | MCT First Disclosures Brehmer, Dirk Beke, Lijs Wu, Tongfei Millar, Hillary J. Moy, Christopher Sun, Weimei Mannens, Geert Pande, Vineet Boeckx, An van Heerde, Erika Nys, Thomas Gustin, Emmanuel M. Verbist, Bie Zhou, Longen Fan, Yue Bhargava, Vipul Safabakhsh, Pegah Vinken, Petra Verhulst, Tinne Gilbert, Angelique Rai, Sumit Graubert, Timothy A. Pastore, Friederike Fiore, Danilo Gu, Junchen Johnson, Amy Philippar, Ulrike Morschhäuser, Barbara Walker, David De Lange, Desiree Keersmaekers, Vikki Viellevoye, Marcel Diels, Gaston Schepens, Wim Thuring, Jan Willem Meerpoel, Lieven Packman, Kathryn Lorenzi, Matthew V. Laquerre, Sylvie Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity |
title | Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity |
title_full | Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity |
title_fullStr | Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity |
title_full_unstemmed | Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity |
title_short | Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity |
title_sort | discovery and pharmacological characterization of jnj-64619178, a novel small-molecule inhibitor of prmt5 with potent antitumor activity |
topic | MCT First Disclosures |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9398174/ https://www.ncbi.nlm.nih.gov/pubmed/34583982 http://dx.doi.org/10.1158/1535-7163.MCT-21-0367 |
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