The novel retinoid WYC-209 sensitizes multiple myeloma to carfilzomib via epigenetically upregulating ZMYND8.

Carfilzomib (CFZ) is a cornerstone therapy for patients with relapsed multiple myeloma (MM); however, poor prolonged treatment response remains a major clinical limitation. ZMYND8 overexpression increases the sensitivity of MM cells to CFZ. Therefore, pharmacological activation of ZMYND8 may offer an emerging strategy to improve CFZ efficacy. In this study, we identified a novel retinoic acid analog, WYC-209, as an epigenetic activator of ZMYND8 expression in MM cells. The additive cytotoxic effects of WYC-209 and CFZ were analyzed using flow cytometry, transmission electron microscopy, and drug synergy assays. The in vivo therapeutic synergy was assessed in a mouse xenograft model using tumor burden and survival analysis. We found that both all-trans retinoic acid (ATRA) and WYC-209 significantly upregulated the transcriptional expression of ZMYND8 by remodeling the epigenetic landscape, particularly via H3K27ac. Combined treatment with CFZ and either ATRA or WYC-209 exhibited pronounced synergistic effects in killing primary MM cells. Moreover, WYC-209 synergized with CFZ to inhibit cell viability, induce apoptosis, and exacerbate endoplasmic reticulum dilation in MM cells, whereas the depletion of ZMYND8 markedly attenuated these effects. In vivo experiments confirmed that WYC-209 potentiated the antitumor efficacy of CFZ by upregulating ZMYND8, thereby ameliorating tumor burden in NSG mice. These findings establish that targeting ZMYND8 with the novel retinoid WYC-209 potently enhances the efficacy of CFZ and holds translational promise for improving clinical outcomes in patients with MM.