Discovery of Potent Isoindolinone Inhibitors That Target an Active Conformation of PARP1 Using DNA‐Encoded Libraries

Inhibition of poly (ADP‐ribose) polymerase‐1 (PARP1), a DNA repair enzyme, has proven to be a successful strategy for the treatment of various cancers. With the appropriate selection conditions and protein design, DNA‐encoded library (DEL) technology provides a powerful avenue to identify small molecules with the desired mechanism of action towards a target of interest. However, DNA‐binding proteins, such as PARP1, can be challenging targets for DEL screening due to non‐specific protein‐DNA interactions. To overcome this, we designed and screened a PARP1 catalytic domain construct without the autoinhibitory helical domain. This allowed us to interrogate an active, functionally‐relevant form of the protein resulting in the discovery of novel isoindolinone PARP1 inhibitors with single‐digit nanomolar potency. These inhibitors also demonstrated little to no PARP1‐DNA trapping, a property that could be advantageous in the clinic.