Discovery of Potent Isoindolinone Inhibitors that Target an Active Conformation of PARP1 Using DNA-Encoded Libraries

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Poly (ADP-ribose) polymerase-1 (PARP1) is a DNA repair enzyme crucial in cancer treatment.
• DNA-encoded library (DEL) technology is effective for identifying small molecule inhibitors.
• DNA-binding proteins like PARP1 present challenges for DEL screening due to non-specific interactions.

Purpose of the Study:

• To overcome challenges in screening DNA-binding proteins using DEL technology.
• To identify novel small molecule inhibitors of PARP1.
• To discover inhibitors with desirable clinical properties, such as reduced DNA trapping.

Main Methods:

• Designed and screened a modified PARP1 catalytic domain construct lacking the autoinhibitory helical domain.
• Utilized DNA-encoded library (DEL) technology for high-throughput screening.
• Characterized the potency and DNA-trapping properties of identified inhibitors.

Main Results:

• Discovered novel isoindolinone PARP1 inhibitors with single-digit nanomolar potency.
• The identified inhibitors exhibited minimal to no PARP1-DNA trapping.
• The modified PARP1 construct enabled effective screening of an active protein form.

Conclusions:

• A modified PARP1 construct facilitates DEL screening of challenging DNA-binding targets.
• Novel, potent PARP1 inhibitors with reduced DNA trapping were identified.
• These findings offer a promising new avenue for cancer therapy development.