Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity

Sheng Wang, Sebastian O. Klein, Sylvia Urban, Maximilian Staudt, Nicolas P. F. Barthes, Dominica Willmann, Johannes Bacher, Manuela Sum, Helena Bauer, Ling Peng, Georg A. Rennar, Christian Gratzke, Katrin M. Schüle, Lin Zhang, Oliver Einsle, Holger Greschik, Calum MacLeod, Christopher G. Thomson, Manfred Jung, Eric Metzger () and Roland Schüle ()
Additional contact information
Sheng Wang: Klinikum der Albert-Ludwigs-Universität Freiburg
Sebastian O. Klein: University of Freiburg
Sylvia Urban: Klinikum der Albert-Ludwigs-Universität Freiburg
Maximilian Staudt: Albert-Ludwigs-Universität Freiburg
Nicolas P. F. Barthes: Albert-Ludwigs-Universität Freiburg
Dominica Willmann: Klinikum der Albert-Ludwigs-Universität Freiburg
Johannes Bacher: Albert-Ludwigs-Universität Freiburg
Manuela Sum: Klinikum der Albert-Ludwigs-Universität Freiburg
Helena Bauer: Klinikum der Albert-Ludwigs-Universität Freiburg
Ling Peng: Klinikum der Albert-Ludwigs-Universität Freiburg
Georg A. Rennar: Albert-Ludwigs-Universität Freiburg
Christian Gratzke: Klinikum der Albert-Ludwigs-Universität Freiburg
Katrin M. Schüle: Faculty of Medicine, University of Freiburg
Lin Zhang: Albert-Ludwigs-Universität Freiburg
Oliver Einsle: Albert-Ludwigs-Universität Freiburg
Holger Greschik: Klinikum der Albert-Ludwigs-Universität Freiburg
Calum MacLeod: Drug Discovery, Pharmaron UK Ltd
Christopher G. Thomson: Drug Discovery, Pharmaron UK Ltd
Manfred Jung: University of Freiburg
Eric Metzger: Klinikum der Albert-Ludwigs-Universität Freiburg
Roland Schüle: Klinikum der Albert-Ludwigs-Universität Freiburg

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Inhibition of epigenetic regulators by small molecules is an attractive strategy for cancer treatment. Recently, we characterised the role of lysine methyltransferase 9 (KMT9) in prostate, lung, and colon cancer. Our observation that the enzymatic activity was required for tumour cell proliferation identified KMT9 as a potential therapeutic target. Here, we report the development of a potent and selective KMT9 inhibitor (compound 4, KMI169) with cellular activity through structure-based drug design. KMI169 functions as a bi-substrate inhibitor targeting the SAM and substrate binding pockets of KMT9 and exhibits high potency, selectivity, and cellular target engagement. KMT9 inhibition selectively downregulates target genes involved in cell cycle regulation and impairs proliferation of tumours cells including castration- and enzalutamide-resistant prostate cancer cells. KMI169 represents a valuable tool to probe cellular KMT9 functions and paves the way for the development of clinical candidate inhibitors as therapeutic options to treat malignancies such as therapy-resistant prostate cancer.

Date: 2024
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DOI: 10.1038/s41467-023-44243-6

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