Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity

Epigenetic therapies have emerged as an up-and-coming strategy avenue for treating cancer treatmentmalignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by merging pharmacophores. Among them, compound (R)-23a stood out due to balanced inhibition of DNMT1 and HDAC, along with excellent anti-tumor effects in vitro by stimulating both histone acetylation and DNA methylation. Notably, treatment with compound (R)-23a resulted in a significant anti-tumor effect (TGI = 98%) on MV-4-11 xenograft models, surpassing that achieved with combination therapy. Additionally, compound (R)-23a demonstrated the ability to dramatically reduce tumor volume or even induce tumor regression in MC38 murine colon cancer models. However, this effect was compromised under conditions of immune deficiency. In conclusion, the novel DNMT1/HDAC dual inhibitor (R)-23a holds promise for the development of multiple-target anti-AML agents and tumor immunotherapy. To decipher the molecular mechanism underlying the enhanced anti-AML activities of (R)-23a, we conducted RNA sequencing (RNA-seq) on MV-4-11 cells treated with (R)-23a, GSK5032, SAHA, and the combination of GSK5032 and SAHA (COMBO).