Small molecule MBD2 pathway inhibitor KCC-07 suppresses breast cancer cell fitness

Elevated expression of the DNA methylation reader methyl-CpG-binding domain protein 2 (MBD2) reprograms the transcriptional landscape of cancer cells to promote proliferation and invasion. Despite its emerging importance in cancer biology, pharmacological targeting of MBD2 to treat cancer is underexplored because of the presence of intrinsically disordered regions, which confound drug discovery. Here, we pharmacologically target MBD2 using KCC-07, a small-molecule inhibitor that blocks its DNA-binding ability, to evaluate its therapeutic potential in well-established in vitro and in vivo models of breast cancer. We found that KCC-07 administration caused a dose-dependent decrease in proliferative and clonogenic survival capabilities of mouse PyMT-R221A and E0771 breast cancer cells and substantially reduced their invasiveness in vitro. The anti-cancer effects of KCC-07 were further validated in vivo, where it markedly reduced the growth of orthotopic PyMT-R221A primary breast tumors in immunocompetent mice compared to the controls. In contrast, KCC-07 treatment neither prevented nor reduced lung colonization by PyMT-R221A cells in an experimental lung colonization model. Biochemical analyses of blood from KCC-07-treated mice showed no hepatotoxicity or nephrotoxicity. Transcriptomic analyses revealed that KCC-07 treatment upregulated the p53-associated gene expression program, which likely mediates its anti-cancer effects. Overall, our findings suggest that KCC-07, with its high selectivity, could be a promising therapeutic modality for treating primary tumors with elevated MBD2 expression.