2. Academic Validation
  3. Development of High-Affinity CHD1 Chromodomain Inhibitors

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

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z