Delving into the Latest Updates on Onametostat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PRMT5

Mechanism

PRMT5 inhibitors(Protein arginine methyltransferase 5 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication

Microsatellite Instability cancerAdvanced cancerAdvanced Malignant Solid Neoplasm+ [2]

Inactive Indication-

Originator Organization

Janssen Research & Development LLC

Active Organization

Janssen Research & Development LLCJanssen R&D Ireland Ltd.

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H23BrN6O2

InChIKeyDBSMLQTUDJVICQ-CJODITQLSA-N

CAS Registry2086772-26-9

The purpose of the study is to identify the maximum tolerated dose (MTD) of JNJ-64619178 in participants with relapsed/refractory B cell non-Hodgkin lymphoma (NHL) or advanced solid tumors and also to identify the recommended Phase 2 dose(s) (RP2Ds) of JNJ-64619178 for NHL and advanced solid tumors (Part 1) and to confirm the tolerability of JNJ-64619178 in participants with lower risk myelodysplastic syndromes (MDS) (Part 2).

Start Date13 Jul 2018

Sponsor / Collaborator

Janssen Research & Development LLC

100 Clinical Results associated with Onametostat

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100 Translational Medicine associated with Onametostat

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100 Patents (Medical) associated with Onametostat

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14

Literatures (Medical) associated with Onametostat

01 Jan 2025·European Journal of Medicinal Chemistry

One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors

Article

Author: Zhang, Ying ; Liu, Li ; Chen, Zhong-Zhu ; Wang, Chang-Yun ; Yang, Hong ; Liu, Zhiqing ; Li, Huaxuan ; Huang, Xun ; Zhang, Jian ; Li, Bang ; Wang, Yuanxiang ; Wang, Xingcan ; Zheng, Jiahong ; Zhou, Ruilin ; Shi, Qiongyu

The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets. The representative compound 36 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound 36 potently reduced the level of symmetric dimethylarginines (sDMA) and inhibited the proliferation of MOLM-13 cell lines by inducing apoptosis and cell cycle arrest. Moreover, compound 36 had more favorable metabolic stability and aqueous solubility than JNJ64619178 (9). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that 36 is a highly potent and selective PRMT5 inhibitor worthy for further development.

08 Oct 2024·Antimicrobial Agents and Chemotherapy

Onametostat, a PfPRMT5 inhibitor, exhibits antimalarial activity to Plasmodium falciparum

Article

Author: Madsen, Jesper J. ; Chim-Ong, Anongruk ; Lucky, Amuza Byaruhanga ; Miao, Jun ; Min, Hui ; Cui, Liwang ; Li, Xiaolian

ABSTRACT Protein arginine methyltransferases (PRMTs) play critical roles in Plasmodium falciparum , a protozoan causing the deadliest form of malaria, making them potential targets for novel antimalarial drugs. Here, we screened 11 novel PRMT inhibitors against P. falciparum asexual growth and found that onametostat, an inhibitor for type II PRMTs, exhibited strong antimalarial activity with a half-maximal inhibitory concentration (IC 50 ) value of 1.69 ± 0.04 µM. In vitro methyltransferase activities of purified PfPRMT5 were inhibited by onametostat, and a shift of IC 50 to onametostat was found in the PfPRTM5 disruptant parasite line, indicating that PfPRTM5 is the primary target of onametostat. Consistent with the function of PfPRMT5 in mediating symmetric dimethylation of histone H3R2 (H3R2me2s) and in regulating invasion-related genes, onametostat treatment led to the reduction of H3R2me2s level in P. falciparum and caused the defects on the parasite’s invasion of red blood cells. This study provides a starting point for identifying specific PRMT inhibitors with the potential to serve as novel antimalarial drugs.

29 Jan 2024·Oncogene

MYCN and SNRPD3 cooperate to maintain a balance of alternative splicing events that drives neuroblastoma progression

Article

Author: Jayatilleke, Nisitha ; Cheung, Belamy B ; Speleman, Frank ; Mayoh, Chelsea ; Salib, Alice ; Seneviratne, Janith A ; De Preter, Katleen ; Marshall, Glenn M ; Carter, Daniel R

AbstractMany of the pro-tumorigenic functions of the oncogene MYCN are attributed to its regulation of global gene expression programs. Alternative splicing is another important regulator of gene expression and has been implicated in neuroblastoma development, however, the molecular mechanisms remain unknown. We found that MYCN up-regulated the expression of the core spliceosomal protein, SNRPD3, in models of neuroblastoma initiation and progression. High mRNA expression of SNRPD3 in human neuroblastoma tissues was a strong, independent prognostic factor for poor patient outcome. Repression of SNRPD3 expression correlated with loss of colony formation in vitro and reduced tumorigenicity in vivo. The effect of SNRPD3 on cell viability was in part dependent on MYCN as an oncogenic co-factor. RNA-sequencing revealed a global increase in the number of genes being differentially spliced when MYCN was overexpressed. Surprisingly, depletion of SNRPD3 in the presence of overexpressed MYCN further increased differential splicing, particularly of cell cycle regulators, such as BIRC5 and CDK10. MYCN directly bound SNRPD3, and the protein arginine methyltransferase, PRMT5, consequently increasing SNRPD3 methylation. Indeed, the PRMT5 inhibitor, JNJ-64619178, reduced cell viability and SNRPD3 methylation in neuroblastoma cells with high SNRPD3 and MYCN expression. Our findings demonstrate a functional relationship between MYCN and SNRPD3, which maintains the fidelity of MYCN-driven alternative splicing in the narrow range required for neuroblastoma cell growth. SNRPD3 methylation and its protein-protein interface with MYCN represent novel therapeutic targets.

100 Deals associated with Onametostat

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Myelodysplastic Syndromes	Phase 1	US	Janssen Research & Development LLC	13 Jul 2018
Myelodysplastic Syndromes	Phase 1	ES	Janssen Research & Development LLC	13 Jul 2018
Myelodysplastic Syndromes	Phase 1	DE	Janssen Research & Development LLC	13 Jul 2018
Myelodysplastic Syndromes	Phase 1	CA	Janssen Research & Development LLC	13 Jul 2018
Myelodysplastic Syndromes	Phase 1	IL	Janssen Research & Development LLC	13 Jul 2018
Non-Hodgkin Lymphoma	Phase 1	US	Janssen Research & Development LLC	13 Jul 2018
Non-Hodgkin Lymphoma	Phase 1	IL	Janssen Research & Development LLC	13 Jul 2018
Non-Hodgkin Lymphoma	Phase 1	ES	Janssen Research & Development LLC	13 Jul 2018
Non-Hodgkin Lymphoma	Phase 1	DE	Janssen Research & Development LLC	13 Jul 2018
Non-Hodgkin Lymphoma	Phase 1	CA	Janssen Research & Development LLC	13 Jul 2018

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03573310 (ESMO2020) Manual	Phase 1	Advanced cancer	54	JNJ-64619178	(qzxqhictpa) = thrombocytopenia, at 3 and 4 mg intermittently and 2 mg QD zpslmhiwkx (snzoamihfi ) View more	Positive	18 Sep 2020