2. Academic Validation
  3. Discovery of a novel class NSD2 inhibitor for multiple myeloma with t(4;14)

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

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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