2. Academic Validation
  3. Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity

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

  • Nat Commun. 2024 Jan 2;15(1):43. doi: 10.1038/s41467-023-44243-6.
Sheng Wang 1,  Sebastian O Klein 2,  Sylvia Urban 1,  Maximilian Staudt 3,  Nicolas P F Barthes 3,  Dominica Willmann 1,  Johannes Bacher 3,  Manuela Sum 1,  Helena Bauer 1,  Ling Peng 1,  Georg A Rennar 3,  Christian Gratzke 1,  Katrin M Schüle 4,  Lin Zhang 5,  Oliver Einsle 5,  Holger Greschik 1,  Calum MacLeod 6,  Christopher G Thomson 6,  Manfred Jung 2 3 7,  Eric Metzger 8 9,  Roland Schüle 10 11 12
Affiliations

Affiliations

  • 1 Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 2 CIBSS Centre of Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
  • 3 Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 4 Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 5 Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 6 Drug Discovery, Pharmaron UK Ltd, Hoddesdon, United Kingdom.
  • 7 Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg, Freiburg, Germany.
  • 8 Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Albert-Ludwigs-Universität Freiburg, Freiburg, Germany. eric.metzger@uniklinik-freiburg.de.
  • 9 Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg, Freiburg, Germany. eric.metzger@uniklinik-freiburg.de.
  • 10 Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Albert-Ludwigs-Universität Freiburg, Freiburg, Germany. roland.schuele@uniklinik-freiburg.de.
  • 11 CIBSS Centre of Biological Signalling Studies, University of Freiburg, Freiburg, Germany. roland.schuele@uniklinik-freiburg.de.
  • 12 Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg, Freiburg, Germany. roland.schuele@uniklinik-freiburg.de.
PMID: 38167811 DOI: 10.1038/s41467-023-44243-6
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157486
    98.00%, KMT9 Inhibitor