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

  • Blood Neoplasia. 2025 Mar 11;2(2):100091. doi: 10.1016/j.bneo.2025.100091.
Sae Matsuoka  1 ,  Naoki Osada  1 ,  Hirokazu Kubota  2 ,  Ko Kikuzato  2 ,  Hiroo Koyama  2 ,  Takeshi Sonoda  3 ,  Akiko Idei  3 ,  Minoru Yoshida  3  4 ,  Masaki Kikuchi  5 ,  Takashi Umehara  5 ,  Chiduru Watanabe  6 ,  Teruki Honma  6 ,  Hiroshi Yasui  7  8 ,  Sho Ikeda  9 ,  Naoto Takahashi  9 ,  Hideki Nakasone  1 ,  Jiro Kikuchi  1 ,  Yusuke Furukawa  1  10  11
Affiliations
  • 1. Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
  • 2. Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Wako, Japan.
  • 3. Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, Wako, Japan.
  • 4. Office of University Professors, The University of Tokyo, Tokyo, Japan.
  • 5. Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan.
  • 6. Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan.
  • 7. Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 8. Department of Hematology and Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
  • 9. Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
  • 10. Center for Medical Education, Teikyo University of Science, Tokyo, Japan.
  • 11. Drug Discovery Cooperation Division, RIKEN Program for Drug Discovery and Medical Technology Platform, Yokohama, Japan.
PMID: 40949769 DOI: 10.1016/j.bneo.2025.100091
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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