{"title":"发现一种新型NSD2抑制剂治疗t(4;14)+多发性骨髓瘤","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","doi":"10.1016/j.bneo.2025.100091","DOIUrl":null,"url":null,"abstract":"<div><h3>Abstract</h3><div>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)<sup>+</sup> MM compared with t(4;14)<sup>-</sup> MM cells in vitro and in vivo via transcriptional suppression of the <em>IRF4</em> 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).</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 2","pages":"Article 100091"},"PeriodicalIF":0.0000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+\",\"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\",\"doi\":\"10.1016/j.bneo.2025.100091\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Abstract</h3><div>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)<sup>+</sup> MM compared with t(4;14)<sup>-</sup> MM cells in vitro and in vivo via transcriptional suppression of the <em>IRF4</em> 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).</div></div>\",\"PeriodicalId\":100189,\"journal\":{\"name\":\"Blood Neoplasia\",\"volume\":\"2 2\",\"pages\":\"Article 100091\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Blood Neoplasia\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2950328025000263\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Neoplasia","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2950328025000263","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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).