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Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)
Sae Matsuoka1, Naoki Osada1, Hirokazu Kubota2
1Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
Abstract:
The prognosis for multiple myeloma (MM) has continued to improve with the development of a series of novel molecular targeted drugs over time. However, the prognosis remains poor for cases with high-risk chromosomal abnormalities. Of such abnormalities, t(4;14) is the second most common, occurring in 15% of patients with MM. MM cells carrying t(4;14) strongly express histone methyltransferase with a SET domain, called NSD2, making them resistant to drugs against MM. Therefore, NSD2 is a promising therapeutic target for MM carrying t(4;14). Subsequently, we performed high-throughput screening and identified RK-0080552 (RK-552) as a novel class NSD2 inhibitor. RK-552 was significantly cytotoxic against t(4;14)+ MM compared with t(4;14)- MM cells in vitro and in vivo via transcriptional suppression of the IRF4 gene, coincided with a decrease in histone H3 lysine 36 dimethylation. Moreover, RK-552 acted additively with pomalidomide in vitro and prolonged the survival of recipient mice without side effects. These results suggest that RK-552 may be a clinically relevant NSD2 inhibitor with specific cytotoxicity to MM cells carrying t(4;14). Our study also provides a molecular basis and rationale for the inclusion in current treatment strategies. Therefore, the clinical use of RK-552 may significantly improve the treatment outcome of MM with t(4;14).
Insights
A new drug, RK-552, effectively targets NSD2 in multiple myeloma (MM) with the t(4;14) abnormality. This targeted therapy shows promise for improving patient outcomes in this high-risk MM subtype.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma (MM) prognosis is improving, but high-risk chromosomal abnormalities like t(4;14) confer poor outcomes.
- The t(4;14) abnormality in MM leads to overexpression of NSD2, a histone methyltransferase, contributing to drug resistance.
Purpose of the Study:
- To identify and characterize novel therapeutic agents targeting NSD2 in MM.
- To evaluate the efficacy and mechanism of action of the identified NSD2 inhibitor, RK-552.
Main Methods:
- High-throughput screening was employed to identify NSD2 inhibitors.
- In vitro and in vivo studies were conducted to assess RK-552's cytotoxicity and mechanism.
- RK-552 was tested in combination with pomalidomide.
Main Results:
- RK-552 was identified as a novel NSD2 inhibitor.
- RK-552 demonstrated significant cytotoxicity against t(4;14)+ MM cells by suppressing IRF4 transcription and decreasing histone H3 lysine 36 dimethylation.
- RK-552 showed additive effects with pomalidomide and prolonged survival in vivo without observed side effects.
Conclusions:
- RK-552 is a potent and specific NSD2 inhibitor with promising therapeutic potential for t(4;14)+ MM.
- The findings provide a molecular rationale for incorporating RK-552 into MM treatment strategies.
- RK-552 may significantly improve treatment outcomes for patients with t(4;14) MM.
