Development of High-Affinity CHD1 Chromodomain Inhibitors.

Area of Science:

• Biochemistry
• Epigenetics
• Medicinal Chemistry

Background:

• Chromatin remodeler CHD1 regulates gene activity and is a potential therapeutic target in prostate cancer (PCa).
• CHD1 possesses a tandem chromodomain (tCD) that binds histone H3 trimethylated at lysine 4 (H3K4me3).

Purpose of the Study:

• To develop and characterize novel, potent inhibitors targeting the H3K4me3 binding site of the CHD1 tCD.
• To investigate the binding mode and selectivity of these inhibitors.
• To assess the potential of these inhibitors in modulating PCa cell viability.

Main Methods:

• Development of submicromolar quinoline-based inhibitors (2n and 2s).
• Co-crystal structure determination to elucidate ligand-protein interactions.
• Biochemical assays to determine binding affinity (Kd) and selectivity against other epigenetic enzymes.
• Cellular assays to assess engagement with endogenous CHD1 and impact on PCa cell viability.

Main Results:

• Compounds 2n and 2s exhibit submicromolar inhibitory activity against CHD1 tCD (Kd values of 0.15 μM and 0.14 μM, respectively).
• Co-crystal structures reveal key interactions, including aromatic cage formation, driving high-affinity binding.
• Inhibitors engage endogenous CHD1 in cell lysates and exogenous CHD1 in cells, demonstrating cellular activity.
• Compounds show selectivity against a panel of methyl-lysine readers and epigenetic enzymes.
• Inhibition of CHD1 by 2n and 2s leads to impaired PCa cell viability.

Conclusions:

• Novel quinoline-based inhibitors (2n and 2s) with high potency and selectivity for the CHD1 tCD H3K4me3 binding site have been developed.
• The defined binding mode provides a foundation for further optimization of CHD1 inhibitors.
• These potent ligands represent promising leads for the development of novel therapeutics for prostate cancer.