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: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Blood Neoplasia |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950328025000263 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sae Matsuoka |
| collection | DOAJ |
| description | 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). |
| format | Article |
| id | doaj-art-db0fe078bbfc4331aaa8a3d2cd9c6e6b |
| institution | Kabale University |
| issn | 2950-3280 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Neoplasia |
| spelling | doaj-art-db0fe078bbfc4331aaa8a3d2cd9c6e6b2025-08-20T03:48:46ZengElsevierBlood Neoplasia2950-32802025-05-012210009110.1016/j.bneo.2025.100091Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+Sae Matsuoka0Naoki Osada1Hirokazu Kubota2Ko Kikuzato3Hiroo Koyama4Takeshi Sonoda5Akiko Idei6Minoru Yoshida7Masaki Kikuchi8Takashi Umehara9Chiduru Watanabe10Teruki Honma11Hiroshi Yasui12Sho Ikeda13Naoto Takahashi14Hideki Nakasone15Jiro Kikuchi16Yusuke Furukawa17Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, JapanDivision of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, JapanDrug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Wako, JapanDrug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Wako, JapanDrug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Wako, JapanDrug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, Wako, JapanDrug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, Wako, JapanDrug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, Wako, Japan; Office of University Professors, The University of Tokyo, Tokyo, JapanLaboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, Yokohama, JapanLaboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, Yokohama, JapanDrug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research, Yokohama, JapanDrug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research, Yokohama, JapanInstitute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Hematology and Oncology, St. Marianna University School of Medicine, Kawasaki, JapanDepartment of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, JapanDepartment of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, JapanDivision of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, JapanDivision of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan; Correspondence: Jiro Kikuchi, Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan;Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan; Center for Medical Education, Teikyo University of Science, Tokyo, Japan; Drug Discovery Cooperation Division, RIKEN Program for Drug Discovery and Medical Technology Platform, Yokohama, JapanAbstract: 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).http://www.sciencedirect.com/science/article/pii/S2950328025000263 |
| spellingShingle | 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 Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+ Blood Neoplasia |
| title | Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+ |
| title_full | Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+ |
| title_fullStr | Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+ |
| title_full_unstemmed | Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+ |
| title_short | Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)+ |
| title_sort | discovery of a novel class nsd2 inhibitor for multiple myeloma with t 4 14 |
| url | http://www.sciencedirect.com/science/article/pii/S2950328025000263 |
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