RESUMO
Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.
Assuntos
Ciclopropanos/farmacologia , Glicosídeo Hidrolases/toxicidade , Microssomos Hepáticos/efeitos dos fármacos , Administração Oral , Animais , Ciclopropanos/administração & dosagem , Ciclopropanos/química , Ciclopropanos/farmacocinética , Glicosídeo Hidrolases/administração & dosagem , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/farmacocinética , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismoRESUMO
DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors.
Assuntos
Reparo do DNA , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Quinazolinonas/química , Quinazolinonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Domínio Catalítico , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Inibidores de Glicosídeo Hidrolases/farmacocinética , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/metabolismo , Células HeLa , Humanos , Masculino , Camundongos , Modelos Moleculares , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
The enzyme poly(ADP-ribose) glycohydrolase (PARG) performs a critical role in the repair of DNA single strand breaks (SSBs). However, a detailed understanding of its mechanism of action has been hampered by a lack of credible, cell-active chemical probes. Herein, we demonstrate inhibition of PARG with a small molecule, leading to poly(ADP-ribose) (PAR) chain persistence in intact cells. Moreover, we describe two advanced, and chemically distinct, cell-active tool compounds with convincing on-target pharmacology and selectivity. Using one of these tool compounds, we demonstrate pharmacology consistent with PARG inhibition. Further, while the roles of PARG and poly(ADP-ribose) polymerase (PARP) are closely intertwined, we demonstrate that the pharmacology of a PARG inhibitor differs from that observed with the more thoroughly studied PARP inhibitor olaparib. We believe that these tools will facilitate a wider understanding of this important component of DNA repair and may enable the development of novel therapeutic agents exploiting the critical dependence of tumors on the DNA damage response (DDR).