Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+

Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+

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, o...

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Main Authors: Sae Matsuoka, Naoki Osada, Hirokazu Kubota, Ko Kikuzato, Hiroo Koyama, Takeshi Sonoda, Akiko Idei, Minoru Yoshida, Masaki Kikuchi, Takashi Umehara, Chiduru Watanabe, Teruki Honma, Hiroshi Yasui, Sho Ikeda, Naoto Takahashi, Hideki Nakasone, Jiro Kikuchi, Yusuke Furukawa
Format: Article
Language:English
Published: Elsevier 2025-05-01
Series:Blood Neoplasia
Online Access:http://www.sciencedirect.com/science/article/pii/S2950328025000263
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Summary: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).
ISSN:2950-3280

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