Structure and mechanism of inhibition of lysine demethylase 2A (KDM2A) by compound 183c

Here we investigated the mechanism of compound 183c, a potent KDM2A inhibitor described in the patent literature. Biophysical studies showed that 183c requires the co-factor 2-oxoglutarate (2OG) for binding.

A 2.2 Å crystal structure of the KDM2A–183c–2OG ternary complex explained the selectivity of 183c and revealed how 183c occupies the H3K36me2 substrate pocket, with a crucial group mimicking dimethylated lysine 36. In proliferation assays, several ALT-positive cell lines were selectively sensitive to 183c. Comparing ALT-positive SAOS2 and ALT-negative SJSA1 cells, both showed repression of E2F-regulated genes, but only SJSA1 activated EMT, DNA repair, and mTOR pathways, indicating distinct adaptive responses.