The validation of new CHD1L inhibitors as a therapeutic strategy for cancer

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Chromodomain helicase DNA-binding protein 1 like (CHD1L) is an oncogene implicated in tumor progression, metastasis, and multidrug resistance.
• Elevated CHD1L expression correlates with poor patient outcomes across various cancer types.
• Targeting CHD1L represents a potential therapeutic strategy for cancer treatment.

Purpose of the Study:

• To discover and characterize novel inhibitors of CHD1L (CHD1Li).
• To evaluate the bioactivity, metabolic stability, and binding characteristics of identified CHD1Li.
• To explore the therapeutic potential of CHD1Li as targeted agents for colorectal and other cancers.

Main Methods:

• High-throughput screening was employed to identify initial CHD1L inhibitors.
• Enzyme inhibition assays, 3D tumor organoid cytotoxicity assays, and mechanistic studies were performed.
• Metabolic stability was assessed using human and mouse liver microsomes.
• Molecular modeling was utilized to elucidate drug-target interactions.

Main Results:

• Structurally distinct compounds 8-11 emerged as potent CHD1L inhibitors from screening.
• Compounds 9 and 11 exhibited favorable metabolic stability in liver microsomes.
• Molecular modeling provided insights into the pharmacophore features responsible for CHD1L binding.
• The identified CHD1Li demonstrate promising bioactivity against the target oncogene.

Conclusions:

• This study expands the chemical diversity of CHD1L inhibitors.
• Compounds 9 and 11 are promising candidates for further development as targeted cancer therapeutics.
• CHD1Li hold potential as a novel targeted therapy for colorectal cancer and other malignancies driven by CHD1L.