2. Academic Validation
  3. Structure-Guided Design of a KMT9 Inhibitor Prodrug with Cellular Activity

Structure-Guided Design of a KMT9 Inhibitor Prodrug with Cellular Activity

  • J Med Chem. 2025 Jul 10;68(13):13295-13320. doi: 10.1021/acs.jmedchem.4c02953.
Sheng Wang 1,  Nicolas P F Barthes 2,  Sylvia Urban 1,  Viktor I Hazai 2,  Sebastian O Klein 2,  Tabea Pappert 2,  Paul Kümmel 2,  Nicolas Heller 2,  Johannes Bacher 2,  Maximilian Staudt 2,  Jan Ruprecht 2,  Ling Peng 1,  Manuela Sum 1,  Christopher Berlin 1,  Daad Sarraf 3,  Pierre Regenass 3,  Robin Warstat 3,  Johannes Walz 3,  Pankaj Mishra 2,  Lin Zhang 4,  Oliver Einsle 4,  Stefan Günther 2,  Bernhard Breit 3,  Eric Metzger 1 5,  Manfred Jung 2 5 6,  Roland Schüle 1 5 6
Affiliations

Affiliations

  • 1 Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Albert-Ludwigs-Universität Freiburg, Freiburg 79106, Germany.
  • 2 Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg 79104, Germany.
  • 3 Institute of Organic Chemistry, Albert-Ludwigs-Universität Freiburg, Freiburg 79104, Germany.
  • 4 Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg 79104, Germany.
  • 5 German Cancer Consortium (DKTK), Partner site Freiburg, A partnership between DKFZ and Medical Center - University of Freiburg, Freiburg 79106, Germany.
  • 6 CIBSS Centre of Biological Signalling Studies, University of Freiburg, Freiburg 79106, Germany.
PMID: 40526927 DOI: 10.1021/acs.jmedchem.4c02953
Abstract

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 8 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.

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