Structure-Guided Design of a KMT9 Inhibitor Prodrug with Cellular Activity
Lysine methyltransferase 9 (KMT9), an obligate heterodimer (KMT9α/KMT9β), belongs to the few described Rossmann-fold histone lysine methyltransferases and monomethylates histone H4 at lysine 12 (H4K12me1). KMT9 depletion or inhibition impairs the proliferation of tumors, including prostate, lung, colon, and bladder cancer cells, underscoring its therapeutic potential. Here, we show the development of branched cofactor analogues with a methionine side chain as highly potent KMT9 inhibitors. Through structure-guided design, a basic nitrogen and 4-chlorophenoxy-2-fluorobenzene in the substrate branch contribute most to the high potency and selectivity. Due to the zwitterionic methionine side chain, the inhibitors did not show cellular activity. Importantly, an ethyl ester prodrug <b>8</b> exhibits cellular target engagement and effectively blocks the proliferation of colon cancer cell lines, further validating pharmacological inhibition of KMT9 as a promising strategy for cancer therapy.
Authors
- Eric Metzger (ORCID: https://orcid.org/0000-0002-1394-1083)
- Stefan Günther (ORCID: https://orcid.org/0000-0003-3744-189X)
- Daad Sarraf (ORCID: https://orcid.org/0000-0002-3922-6643)
- Manfred Jung (ORCID: https://orcid.org/0000-0002-6361-7716)
- Nicolas Barthès (ORCID: https://orcid.org/0000-0002-5102-3056)
- Maximilian Staudt (ORCID: https://orcid.org/0000-0001-5022-4596)
- Pankaj Mishra (ORCID: https://orcid.org/0000-0002-3487-6911)
- Pierre Regenass
- Ling Peng (ORCID: https://orcid.org/0000-0003-2465-9056)
- Robin Warstat
- Manuela Sum
- Christopher Berlin (ORCID: https://orcid.org/0000-0001-9727-1533)
- Viktor Hazai (ORCID: https://orcid.org/0000-0002-4437-0404)
- Oliver Einsle (ORCID: https://orcid.org/0000-0001-8722-2893)
- Bernhard Breit (ORCID: https://orcid.org/0000-0002-2514-3898)
- Roland Schüle
- Sheng Wang (ORCID: https://orcid.org/0000-0002-2813-9878)
- Johannes Bacher
- Lin Zhang (ORCID: https://orcid.org/0000-0001-5431-5006)
- Sebastian O. Klein (ORCID: https://orcid.org/0000-0003-2159-2546)
- Sylvia Urban
- Johannes Walz
- Jan Ruprecht (ORCID: https://orcid.org/0009-0003-2949-0250)
- Nicolas Heller (ORCID: https://orcid.org/0000-0002-7542-6570)
- Paul Kümmel
Institutions
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- University Medical Center Freiburg (DE)
- Klinik und Poliklinik für Urologie (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02953
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft