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

• Published in: ChemMedChem 2024-06, Vol.19 (11), p.e202400093-n/a
• Main Authors: McCarthy, Kelly A., Marcotte, Douglas J., Parelkar, Sangram, McKinnon, Crystal L., Trammell, Lindsay E., Stangeland, Eric L., Jetson, Rachael R.
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Catalytic Domain; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - metabolism; DNA repair; DNA-encoded library; Dose-Response Relationship, Drug; Drug Discovery; Humans; Inhibitors; Isoindoles - chemical synthesis; Isoindoles - chemistry; Isoindoles - pharmacology; Molecular Structure; PARP; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - chemical synthesis; Poly(ADP-ribose) Polymerase Inhibitors - chemistry; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; protein design; Proteins; Ribose; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; structure-activity relationships
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202400093

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. Inhibition of PARP1 is a proven strategy for the treatment of various cancers. We used our DNA‐encoded library platform, comprising ~5 billion molecules, to screen multiple PARP1 protein constructs, including one with the autoinhibitory helical domain removed to mimic a biologically relevant conformation. The experimental design allowed us to find novel and potent isoindolinone PARP1 inhibitors that do not exhibit toxic DNA‐trapping properties.