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Peer-reviewedCC BYCommunications Chemistry

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

  • Pavel Mader1
  • Linshan Liu1
  • Frédéric Vallée2
  • Francois Denis2
  • Victor Pau1
  • Daniel Mao1
  • Lauren Caldwell1
  • Kin Chan1
  • Igor Kurinov3
  • Yael Mamane2
  • Paranjay Parikh4
  • Zemin Zhang1
8 more authors
  • Michel Gallant2
  • Mike Tyers5
  • W. Cameron Black2
  • Michael Zinda6
  • Daniel Durocher1
  • Jeff Wrana1
  • Michal Zimmermann2
  • Frank Sicheri1
6 affiliations
  1. 1Lunenfeld-Tanenbaum Research Institute, Sinai Health System
  2. 2Repare Therapeutics, 7171 Frederick-Banting
  3. 3Department of Chemistry and Chemical Biology, Cornell University, NE-CAT
  4. 4Piramal Discovery Solutions, Pharmaceutical Special Economic Zone
  5. 5The Hospital for Sick Children Research Institute
  6. 6Repare Therapeutics, Suite 1650
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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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Cite

BibTeXRIS
BibTeX
@article{mader2026structure,
  title = {{Structure and mechanism of inhibition of lysine demethylase 2A (KDM2A) by compound 183c}},
  author = {Pavel Mader and Linshan Liu and Frédéric Vallée and Francois Denis and Victor Pau and Daniel Mao and Lauren Caldwell and Kin Chan and Igor Kurinov and Yael Mamane and Paranjay Parikh and Zemin Zhang and Michel Gallant and Mike Tyers and W. Cameron Black and Michael Zinda and Daniel Durocher and Jeff Wrana and Michal Zimmermann and Frank Sicheri},
  journal = {Communications Chemistry},
  year = {2026},
  month = jun,
  doi = {10.1038/s42004-026-02100-9},
  url = {https://doi.org/10.1038/s42004-026-02100-9},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Structure and mechanism of inhibition of lysine demethylase 2A (KDM2A) by compound 183c
AU  - Pavel Mader
AU  - Linshan Liu
AU  - Frédéric Vallée
AU  - Francois Denis
AU  - Victor Pau
AU  - Daniel Mao
AU  - Lauren Caldwell
AU  - Kin Chan
AU  - Igor Kurinov
AU  - Yael Mamane
AU  - Paranjay Parikh
AU  - Zemin Zhang
AU  - Michel Gallant
AU  - Mike Tyers
AU  - W. Cameron Black
AU  - Michael Zinda
AU  - Daniel Durocher
AU  - Jeff Wrana
AU  - Michal Zimmermann
AU  - Frank Sicheri
PY  - 2026
DA  - 2026/06/01
JO  - Communications Chemistry
DO  - 10.1038/s42004-026-02100-9
UR  - https://doi.org/10.1038/s42004-026-02100-9
AB  - 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.
SN  - 2399-3669
ER  -