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

Abstract

PRMT5 is a type II methyltransferase that symmetrically di-methylates arginine residues on proteins involved in signal transduction and cellular transcription. For example, PRMT5 acts as the enzymatic machinery of the methylosome complex, crucial for spliceosome assembly and activity. Although not frequently mutated or amplified in tumors, an elevated PRMT5 protein level that leads to higher methylosome activity and promotes epithelial–mesenchymal transition, has recently been correlated with a poor survival of cancer patients. The PRMT5 inhibitor JNJ-64619178 has been selected as a clinical candidate based on its high selectivity and potency, paired with favorable oral pharmacokinetics and safety properties. JNJ-64619178 binds simultaneously to the SAM- and protein substrate- binding pockets of the PRMT5/MEP50 complex with a pseudo-irreversible mode-of-action. Chemical proteomics, methylomics and RNA-sequencing analyses of PRMT5 inhibitor treated cell line samples support the current biological understanding of PRMT5 as a regulator of alternative splicing events. JNJ-64619178 showed potent and broad inhibition of cellular growth, observed in several cell line panels that represent diverse cancer histologies. Ongoing investigations will explore the potential synthetic lethal correlation between PRMT5 inhibition and cancer driver pathways, including those addicted to altered splicing. Oral administration of JNJ-64619178 resulted in efficient inhibition of di-methylation of SMD1/3 proteins, components of the splicing machinery and direct substrates of the methylosome, in several human NSCLC and SCLC cancer mouse xenograft models. JNJ-64619178 demonstrated dose-dependent tumor growth inhibition and regression in several human NSCLC and SCLC cancer mouse xenograft models with sustained blockage of tumor re-growth after dosing cessation. In summary, JNJ-64619178 has a favorable pre-clinical profile supporting clinical testing in patients with lung cancer and other malignancies. Citation Format: Tongfei Wu, Hillary Millar, Dana Gaffney, Lijs Beke, Geert Mannens, Petra Vinken, Ivan Sommers, Jan-Willem Thuring, Weimei Sun, Christopher Moy, Vineet Pande, Junguo Zhou, Nahor Haddish-Berhane, Mark Salvati, Sylvie Laquerre, Matthew V. Lorenzi, Dirk Brehmer. JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4859.

Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers

“…We confirmed specificity and differential sensitivity to PRMT5 inhibition using a newly available inhibitor, EPZ015938. Using this same inhibitor, Gerhart et al also observe variable sensitivity to PRMT5 inhibition across a panel of 240 cancer cell lines . They find p53 status to be determinant to EPZ015938 sensitivity.…”

“…A newer more potent PRMT5 inhibitor (biochemical IC50 of 6.2 ± 0.8 nmol/L 16 vs 22 ± 14 nmol/L for EPZ015666 27 ), GSK3326595 (EPZ015938), is currently evaluated in a phase I clinical trial. 16,28 In order to confirm the specificity of EPZ015666, we examined its effect on four TNBC cell lines-two sensitive (MDA-MB-453, MDA-MB-468) and two resistant (BT-20, HCC70) to EPZ015666. We first validated the inhibition of PRMT5 activity by EPZ015938 in the four cell lines ( Figure S7A).…”

Chemogenomics for drug discovery: clinical molecules from open access chemical probes

“…263,265 A diverse variety of cancer cell lines were sensitive to treatment with JNJ64619178, with target engagement confirmed by the inhibition of the symmetric arginine dimethylation of SMD1/3 proteins. 261,266,267 In mouse xenograft models of NSCLC, small-cell lung cancer (SCLC), AML, and non-Hodgkin's lymphoma, tumour growth inhibition and regression were observed following once-daily oral dosing at 10 mg kg À1 and sustained post-dosing. These results led Janssen to advance JNJ64619178 to phase I trials in 2018 for the treatment of relapsed/refractory B cell non-Hodgkin lymphoma or advanced solid tumours (NCT03573310).…”

Improving TRAIL-induced apoptosis in cancers by interfering with histone modifications

“…C646 was firstly considered as a p300 and CBP selective inhibitor [91] . However, a recent study shows that Advanced acute leukemia, particularly MLL-r [44] Rearranged mixed lineage leukemia (MLL-r) [45][46][47] CPI-1205 EZH2 1 B-cell lymphomas [48] B-cell lymphomas [49] Tazemetostat (EPZ-6438)…”

“…LSD1 1 Relapsed or refractory SCL C [54] Small cell lung carcinoma [55] JNJ-64619178 Arginine methylation PRMT5 1 Relapsed/refractory B cell non-Hodgkin lymphoma (NHL) or advanced solid tumours Human NSCLC and SCLC cancer mouse xenograft models [49] GSK3326595 (EPZ015938) PRMT5 1 Advanced or metastatic solid tumours and non-Hodgkin's lymphoma [56,57] Hematologic and solid tumour cells lines [58]…”