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

Blood Neoplasia Pub Date : 2025-05-01 DOI:10.1016/j.bneo.2025.100091

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

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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).

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发现一种新型NSD2抑制剂治疗t(4;14)+多发性骨髓瘤

摘要随着一系列新型分子靶向药物的开发，多发性骨髓瘤（multiple myeloma， MM）的预后不断改善。然而，对于高危染色体异常的病例，预后仍然很差。在这些异常中，t（4;14）是第二常见的，发生在15%的MM患者中。携带t（4;14）的MM细胞强烈表达具有SET结构域的组蛋白甲基转移酶，称为NSD2，使其对MM药物产生耐药性。因此，NSD2是携带t的MM的一个有希望的治疗靶点（4;14）。随后，我们进行了高通量筛选，并确定RK-0080552 （RK-552）为新型NSD2抑制剂。与t(4;14)- MM细胞相比，RK-552在体外和体内通过抑制IRF4基因转录对t(4;14)+ MM细胞具有显著的细胞毒性，同时组蛋白H3赖氨酸36二甲基化降低。此外，RK-552在体外与泊马度胺加作用，延长了受体小鼠的生存期，无副作用。这些结果表明，RK-552可能是一种临床相关的NSD2抑制剂，对携带t的MM细胞具有特异性细胞毒性（4;14）。我们的研究也为当前的治疗策略提供了分子基础和基本原理。因此，临床应用RK-552可显著改善MM伴t治疗效果（4;14）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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