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Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials.
- Source :
-
Cancer Letters . Feb2017, p47-56. 10p. - Publication Year :
- 2017
-
Abstract
- Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib. [ABSTRACT FROM AUTHOR]
- Subjects :
- *POLY(ADP-ribose) polymerase
*CLINICAL trials
*ANTINEOPLASTIC agents
*CELL lines
*XENOGRAFTS
*ANIMAL experimentation
*ANTHROPOMETRY
*APOPTOSIS
*BREAST tumors
*CELL physiology
*CELLULAR signal transduction
*COMPARATIVE studies
*DNA
*DOSE-effect relationship in pharmacology
*HAMSTERS
*HETEROCYCLIC compounds
*RESEARCH methodology
*MEDICAL cooperation
*MICE
*ORAL drug administration
*RESEARCH
*TIME
*TRANSFERASES
*EVALUATION research
*BRCA genes
*CANCER cell culture
Subjects
Details
- Language :
- English
- ISSN :
- 03043835
- Database :
- Academic Search Index
- Journal :
- Cancer Letters
- Publication Type :
- Academic Journal
- Accession number :
- 120295357
- Full Text :
- https://doi.org/10.1016/j.canlet.2016.11.010