Open AccessDiscovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity
Author(s) -
Dirk Brehmer,
Lijs Beke,
Tongfei Wu,
Hillary J. Millar,
Christopher Moy,
Weimei Sun,
Geert Mannens,
Vineet Pande,
An Boeckx,
Erika Van Heerde,
Thomas Nys,
Emmanuel Gustin,
Bie Verbist,
Lihua Zhou,
Fan Yang,
Vipul Bhargava,
Pegah Safabakhsh,
Petra Vinken,
Tinne Verhulst,
Angelique Nguyen Gilbert,
Sumit Rai,
Timothy A. Graubert,
Friederike Pastore,
Danilo Fiore,
Junchen Gu,
Amy J. Johnson,
Ulrike Philippar,
Barbara Morschhäuser,
David G. Walker,
Desiree De Lange,
Vikki Keersmaekers,
Marcel Viellevoye,
Gaston Diels,
Wim Schepens,
Jan Willem Thuring,
Lieven Meerpoel,
Kathryn Packman,
Matthew V. Lorenzi,
Sylvie Laquerre
Publication year - 2021
Publication title -
molecular cancer therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.717
H-Index - 173
eISSN - 1538-8514
pISSN - 1535-7163
DOI - 10.1158/1535-7163.mct-21-0367
Subject(s) - protein arginine methyltransferase 5 , cancer research , cancer , lung cancer , in vivo , medicine , breast cancer , biology , pharmacology , methyltransferase , methylation , gene , biochemistry , microbiology and biotechnology
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.