发现一种新型NSD2抑制剂治疗t(4;14)+多发性骨髓瘤

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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摘要

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。
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, 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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