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

  • Commun Chem. 2026 Jun 27. doi: 10.1038/s42004-026-02100-9.
Pavel Mader  1 ,  Linshan Liu  1 ,  Frédéric Vallée  2 ,  Francois Denis  2 ,  Victor Pau  1 ,  Daniel Mao  1 ,  Lauren Caldwell  1 ,  Kin Chan  1 ,  Igor Kurinov  3 ,  Yael Mamane  2 ,  Paranjay Parikh  4 ,  Zemin Zhang  1 ,  Michel Gallant  2 ,  Mike Tyers  5  6 ,  W Cameron Black  2 ,  Michael Zinda  7 ,  Daniel Durocher  1  6 ,  Jeff Wrana  8  9 ,  Michal Zimmermann  10 ,  Frank Sicheri  11  12  13
Affiliations
  • 1. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
  • 2. Repare Therapeutics, 7171 Frederick-Banting, Montréal, QC, Canada.
  • 3. Department of Chemistry and Chemical Biology, Cornell University, NE-CAT, Argonne, IL, USA.
  • 4. Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Ahmedabad, India.
  • 5. The Hospital for Sick Children Research Institute, Toronto, ON, Canada.
  • 6. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 7. Repare Therapeutics, Suite 1650, Cambridge, MA, USA.
  • 8. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. [email protected].
  • 9. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [email protected].
  • 10. Repare Therapeutics, 7171 Frederick-Banting, Montréal, QC, Canada. [email protected].
  • 11. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. [email protected].
  • 12. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [email protected].
  • 13. Department of Biochemistry, University of Toronto, Toronto, ON, Canada. [email protected].
PMID: 42365187 DOI: 10.1038/s42004-026-02100-9
Abstract

Lysine demethylase 2A (KDM2A) is a key epigenetic regulator and promising target for inhibition since its loss is selectively lethal in cancers reliant on Alternative Lengthening of Telomeres (ALT). 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. These structural and cellular insights establish a foundation for designing improved KDM2A inhibitors for ALT-positive cancers.

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