Development of High-Affinity CHD1 Chromodomain Inhibitors

  • J Med Chem. 2026 May 28;69(10):12020-12047. doi: 10.1021/acs.jmedchem.5c03690.
Holger Greschik  1 ,  Florian Friedrich  2 ,  Ludwig Seifert  2 ,  Farnoush Mousavizadeh  3 ,  Francesco Fiorentino  4 ,  Johannes Walz  3 ,  Lin Zhang  5 ,  Jianyu Li  6 ,  Emanuele Fabbrizi  7 ,  Stefano Tomassi  8 ,  Farhad Panahi  3 ,  Niklas Papenkordt  2 ,  Silas L Wurnig  2 ,  Johannes Osterroth  2 ,  Anna M Strasser  2 ,  Jan Ruprecht  2 ,  Aurélien F A Moumbock  6 ,  Martin Hügle  6 ,  Manuela Sum  1 ,  Ling Peng  1 ,  Sheng Wang  1 ,  Adina A Baniahmad  2 ,  Laura Pulido-Cortés  9 ,  H Th Marc Timmers  9 ,  Ralf Flaig  10  11 ,  Eric Metzger  1  9 ,  Bernhard Breit  3 ,  Oliver Einsle  5 ,  Stefan Günther  6 ,  Dante Rotili  12 ,  Antonello Mai  7 ,  Roland Schüle  1  9 ,  Manfred Jung  2  9
Affiliations
  • 1. Department of Urology and Center for Clinical Research, University Freiburg Medical Center, Breisacher Str. 66, 79106 Freiburg, Germany.
  • 2. Institute of Pharmaceutical Sciences, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
  • 3. Institute of Organic Chemistry, University of Freiburg, Albertstr. 21, 70104 Freiburg, Germany.
  • 4. Department of Biochemical Sciences, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.
  • 5. Institute of Biochemistry, University of Freiburg, 79104 Freiburg, Germany.
  • 6. Institute of Pharmaceutical Sciences, University of Freiburg, Hermann-Herder-Str. 9, 79104 Freiburg, Germany.
  • 7. Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.
  • 8. Department of Life Science, Health and Health Professions, LINK Campus University, Via del Casale di San Pio V, 44, CAP 00165 Rome, Italy.
  • 9. German Cancer Consortium (DKTK), Partner Site Freiburg, University Medical Center Freiburg, Breisacher Str. 66, 79106 Freiburg, Germany.
  • 10. Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, Oxfordshire OX11 0DE, United Kingdom.
  • 11. Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot OX11 0FA, United Kingdom.
  • 12. Department of Science, Roma Tre University of Rome, Viale Guglielmo Marconi 446, 00146 Rome, Italy.
PMID: 42085696 DOI: 10.1021/acs.jmedchem.5c03690
Abstract

The chromatin remodeler CHD1, a regulator of gene activity and potential drug target in prostate Cancer (PCa), contains a tandem chromodomain (tCD) binding histone H3 trimethylated at lysine 4 (H3K4me3). We developed the first submicromolar inhibitors (2n and 2s) that target the H3K4me3 binding site of the CHD1 tCD with Kd values of 0.15 μM and 0.14 μM, respectively. Co-crystal structures of these quinoline-based compounds revealed aromatic cage interactions and extended ligand contacts in Other parts of the H3K4me3 peptide pocket as the main determinants of high-affinity ligand binding. 2n and 2s engage endogenous CHD1 in cell lysates or the exogenous CHD1 tCD in cells. Furthermore, we provide evidence for selectivity against a panel of methyl-lysine readers and epigenetic Enzymes as well as impairment of PCa cell viability. Due to their high potency and defined binding mode, our ligands offer new directions for further optimization.

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