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

ChemMedChem. 2024 Mar 14:e202400093. doi: 10.1002/cmdc.202400093. Online ahead of print.ABSTRACTInhibition 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.PMID:38482564 | DOI:10.1002/cmdc.202400093
Source: ChemMedChem - Category: Chemistry Authors: Source Type: research