Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety.
Mol Cancer Ther
; 22(3): 333-342, 2023 03 02.
Article
em En
| MEDLINE
| ID: mdl-36808277
ABSTRACT
PARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Poli(ADP-Ribose) Polimerases
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
/
Male
Idioma:
En
Revista:
Mol Cancer Ther
Assunto da revista:
ANTINEOPLASICOS
Ano de publicação:
2023
Tipo de documento:
Article