Discovery and Characterization of Diverse Non-nucleotide Inhibitors of DNPH1 Using an Integrated Hit Finding Strategy

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• DNPH1 is a hydrolase enzyme that sanitizes nucleotide pools by degrading 5-hydroxymethyl-2'-deoxyuridine 5'-monophosphate (hmdUMP).
• Loss of DNPH1 function sensitizes homologous recombination repair-deficient cancer cells to PARP inhibitors, positioning DNPH1 as a potential therapeutic target.

Purpose of the Study:

• To discover the first non-nucleotide ligands for the DNPH1 enzyme.
• To explore an integrated hit-finding strategy for a challenging novel target.

Main Methods:

• High-throughput screening
• DNA-encoded library screening
• Fragment-based lead generation
• Hit-to-lead optimization

Main Results:

• Discovery of the first non-nucleotide ligands for DNPH1.
• Identification of four distinct hit compounds with varying chemical structures, properties, and binding modes.
• Demonstration of an integrated approach for hit discovery.

Conclusions:

• An integrated hit-finding strategy is effective for discovering ligands against challenging targets like DNPH1.
• The identified non-nucleotide ligands represent promising starting points for developing novel therapeutics targeting DNPH1.