JNJ-64619178 is a Selective PRMT5 Inhibitor with Potent Activity In Lung Cancer
Posted On 2019-04-21
Protein arginine methylation, a common post-translational modification, involves in numerous cellular processes including transcription, DNA repair, mRNA splicing and signal transduction. Protein arginine methyltransferases (PRMTs) catalyze arginine methylation on both chromatin-bound and cytoplasmic proteins. Currently, there are nine protein arginine methyltransferases (PRMTs) encoded in mammalian genomes. Each PRMT isoform harbours the characteristic motifs of the seven-β-strand methyltransferase family.
Additionally, Protein Arginine Methyltransferase 5 (PRMT5) is the major Type II methyltransferase that catalyzes symmetric dimethylarginine. PRMT5 represents a highly conserved arginine methyltransferase that translocates from the cytoplasm to the nucleus. For example, PRMT5 acts as the enzymatic machinery of the methylosome complex, crucial for spliceosome assembly and activity. PRMT5 also induces transcriptional silencing by methylating p53 or MBD2, altering their biochemical functions. Additionally, PRMT5 methylates numerous other proteins regulating normal cell processes. PRMT5 is an attractive drug target in various cancers, and inhibitors are currently in oncological clinical trials.
Moreover, JNJ-64619178 is a PRMT5 selective inhibitor. This active inhibitor has entered clinic trials for multiple cancer types. JNJ-64619178 is a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models. JNJ-64619178 binds simultaneously to the SAM- and protein substrate- binding pockets of the PRMT5/MEP50 complex with a pseudo-irreversible mode-of-action. Moreover, JNJ-64619178 shows potent and broad inhibition of cellular growth, observed in several cell line panels that represent diverse cancer histologies. JNJ-64619178 demonstrates dose-dependent tumor growth inhibition and regression in several human non-small cell lung cancer and small cell lung cancer mouse xenograft models with sustained blockage of tumor regrowth after dosing cessation.
In summary, JNJ-64619178 has a favorable pre-clinical profile supporting clinical testing in several lung cancer models.
Tongfei Wu, et al. Abstract 4859: JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models.
Tao H, et al. Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations. Chem Pharm Bull (Tokyo). 2019;67(4):382-388.