onametostat (JNJ-64619178)

These findings identify a PRMT5-LKB1-AMPK regulatory axis controlling PD-L1 expression in a cell-context-dependent manner and suggest that LKB1 status may serve as a predictive biomarker for combining PRMT5 inhibitors with ICB in NSCLC. This strategy offers a potential therapeutic avenue to overcome immunotherapy resistance in LKB1-proficient NSCLC.

However, PRMT5 inhibitors (e.g., GSK3326595 and JNJ-64619178) demonstrate antitumor effects in preclinical models and methylthioadenosine phosphorylase (MTAP) deletion may serve as a potential biomarker for patient selection. The clinical translation of PRMT5 inhibitors is limited by hematological toxicity, lack of robust predictive biomarkers beyond MTAP and potential resistance from compensatory PRMT family members. It is key to clarify GI cancer-specific PRMT5 mechanisms and potentially develop optimized combination therapies in the future.

P1, N=120, Enrolling by invitation, Janssen Research & Development, LLC | N=52 --> 120

P1, N=52, Enrolling by invitation, Janssen Research & Development, LLC | N=35 --> 52

P1, N=120, Enrolling by invitation, Janssen Research & Development, LLC | N=80 --> 120

P1, N=80, Enrolling by invitation, Janssen Research & Development, LLC | Trial completion date: Jan 2028 --> Oct 2028

Analysis of consensus QSAR models identified two highly active PRMT5 inhibitor candidates (CHEMBL4539612 and CHEMBL4577464), with high affinity for binding (- 13.5 to - 13.7 kcal/mol) to the PRMT5 active site and interactions similar to those of the known clinical PRMT5 inhibitor ONAMETOSTAT...Network pharmacology analysis indicated that PRMT5 and its interacting partners are mainly associated with histone arginine methylation and spliceosomal assembly, processes that are frequently dysregulated in MTAP-deficient cancers. These findings suggest CHEMBL4539612 and CHEMBL4577464 as promising scaffolds for the development of selective PRMT5 inhibitors in epigenetic cancer therapy.

P1, N=114, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Sep 2025 | Trial primary completion date: Dec 2025 --> Sep 2025

P1, N=80, Enrolling by invitation, Janssen Research & Development, LLC

P1, N=114, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

Indeed, the PRMT5 inhibitor, JNJ-64619178, reduced cell viability and SNRPD3 methylation in neuroblastoma cells with high SNRPD3 and MYCN expression...Third, this leads to balanced alterative splicing (AS) activitiy that is favorable to neuroblastoma. Together this forms as a therapeutic vulnerability where SNRPD3 perturbation or PRMT5 inhibitors are selectively toxic to neuroblastoma by conditionally disturbing splicing activity.

A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.