Discovery of Potent Isoindolinone Inhibitors that Target an Active Conformation of PARP1 Using DNA-Encoded Libraries.
ChemMedChem
; 19(11): e202400093, 2024 Jun 03.
Article
em En
| MEDLINE
| ID: mdl-38482564
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
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Inibidores de Poli(ADP-Ribose) Polimerases
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Poli(ADP-Ribose) Polimerase-1
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article