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

Autor: McCarthy KA; Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States., Marcotte DJ; Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States., Parelkar S; Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States., McKinnon CL; Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States., Trammell LE; Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States., Stangeland EL; Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States., Jetson RR; Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Jun 03; Vol. 19 (11), pp. e202400093. Date of Electronic Publication: 2024 Apr 09.
DOI: 10.1002/cmdc.202400093
Abstrakt: 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.
(© 2024 Wiley-VCH GmbH.)
Databáze: MEDLINE
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