Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• DNA polymerase theta (Polθ) is a synthetic lethal target for cancers with BRCA mutations.
• Developing selective Polθ inhibitors is crucial for targeted cancer therapies.

Purpose of the Study:

• To identify and optimize a selective inhibitor of human Polθ (POLQ).
• To evaluate the in vivo efficacy of the lead compound in a relevant cancer model.

Main Methods:

• High-throughput screening of 350,000 compounds to identify initial hits.
• Structure-based drug design and medicinal chemistry optimization.
• Biophysical validation and assessment of cellular potency and ADME properties.

Main Results:

• An initial hit led to the N2-substituted fused pyrazolo series.
• RP-6685 was identified as a potent, selective, and orally bioavailable Polθ inhibitor.
• RP-6685 demonstrated in vivo efficacy in an HCT116 BRCA2-/- mouse tumor xenograft model.

Conclusions:

• RP-6685 is a promising drug candidate for BRCA-mutant cancers.
• The study highlights the potential of Polθ as a therapeutic target.