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

• RK-0080552 is a novel class NSD2 inhibitor that exerts specific cytotoxicity on MM cells carrying t(4;14)

• Down-regulation of IRF4 expression is the molecular basis and rationale for the anti-MM effect of RK-0080552

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)-positive MM compared to t(4;14)-negative MM cells in vitro and in vivo via transcriptional suppression of the IRF4 gene, coincided with a decrease in H3K36 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).