Targeting ATP catalytic activity of chromodomain helicase CHD1L for the anticancer inhibitor discovery

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Chromodomain helicase DNA-binding like 1 (CHD1L) is an ATP-dependent chromatin remodeler implicated in cancer progression.
• Its role in drug resistance and epithelial-mesenchymal transition highlights CHD1L as a potential therapeutic target.

Purpose of the Study:

• To identify novel inhibitors of CHD1L using an integrated approach of deep learning and experimental validation.
• To evaluate the therapeutic potential of identified CHD1L inhibitors against cancer cells.

Main Methods:

• Virtual screening of over 1.5 million small molecules against CHD1L.
• Biochemical assays to assess ATPase activity and binding affinity.
• Cellular experiments to evaluate efficacy in colorectal and breast cancer models.

Main Results:

• Identified 36 candidate compounds, with 13 rigorously evaluated.
• The lead compound, C071-0684, demonstrated potent anticancer activity against colorectal and breast cancer cells.
• C071-0684 showed comparable ATPase activity and binding affinity to existing CHD1L inhibitors, suggesting superior pharmacological potential.

Conclusions:

• C071-0684 is a promising anticancer agent with a novel molecular backbone targeting CHD1L.
• This study provides a foundation for developing novel CHD1L-targeted cancer therapeutics.
• The findings offer hope for improved treatment strategies for cancer patients.