Nature Communications (Jan 2024)

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,
  • Roland Schüle

DOI
https://doi.org/10.1038/s41467-023-44243-6
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 12

Abstract

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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.