KDOBA67 is a novel cell-permeable inhibitor of H3K27 lysine demethylase KDM6A/B, inhibits TBXT expression chordoma cell lines.
KDOBA67 displayed in vitro inhibitory activity in the low micromolar range with IC50 values of 2 to 5 uM in various chordoma cell lines, leading to induction of apoptosis.
H3K27 demethylase inhibition via KDOBA67 alters chromatin state at TBXT and inhibits its expression.
TBXT was a KDM6A/B target gene, and chromatin changes at TBXT following KDOBA67 treatment were associated with a reduction in TBXT protein levels.
KDOBA67 treatment downregulated expression of a network of transcription factors critical for chordoma survival and upregulated pathways dominated by ATF4-driven stress and proapoptotic responses.
