Reference - Detail
| RRC ID | 86618 |
|---|---|
| Author | Matsuoka S, Osada N, Kubota H, Kikuzato K, Koyama H, Sonoda T, Idei A, Yoshida M, Kikuchi M, Umehara T, Watanabe C, Honma T, Yasui H, Ikeda S, Takahashi N, Nakasone H, Kikuchi J, Furukawa Y. |
| Title | Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14). |
| Journal | Blood Neoplasia |
| 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). |
| Volume | 2(2) |
| Pages | 100091 |
| Published | 2025-5-1 |
| DOI | 10.1016/j.bneo.2025.100091 |
| PII | S2950-3280(25)00026-3 |
| PMID | 40949769 |
| PMC | PMC12423681 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 14 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| DNA material | CSII-CMV-MCS-IRES2-Venus (RDB04383) |