Journal ArticleDOI
Dual-target inhibitors of poly (ADP-ribose) polymerase-1 for cancer therapy: Advances, challenges, and opportunities
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TLDR
A recent review summarizes the advance of dual-target PARP1 inhibitors in recent years, focusing on their structural optimization process, structure-activity relationships (SARs), and in vitro or in vivo analysis results as mentioned in this paper .Abstract:
PARP1 plays a crucial role in DNA damage repair, making it an essential target for cancer therapy. PARP1 inhibitors are widely used to treat BRCA-deficient malignancies, and six PARP inhibitors have been approved for clinical use. However, excluding the great clinical success of PARP inhibitors, the concomitant toxicity, drug resistance, and limited scope of application restrict their clinical efficacy. To find solutions to these problems, dual-target inhibitors have shown great potential. In recent years, several studies have linked PAPR1 to other primary cancer targets. Many dual-target inhibitors have been developed using structural fusion, linkage, or library construction methods, overcoming the defects of many single-target inhibitors of PARP1 and achieving great success in clinical cancer therapy. This review summarizes the advance of dual-target PARP1 inhibitors in recent years, focusing on their structural optimization process, structure-activity relationships (SARs), and in vitro or in vivo analysis results. read more
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Journal ArticleDOI
Selective PARP1 Inhibitors, PARP1-based Dual-Target Inhibitors, PROTAC PARP1 Degraders, and Prodrugs of PARP1 Inhibitors for Cancer Therapy.
TL;DR: In this article , a review of the recent progress on PARP-based drug discovery is presented with a focus on the PARP inhibitor-based combination therapy and other PARP1-targeting strategies (e.g., PROTAC degraders, dual acting agents).
Journal ArticleDOI
Design, synthesis, biological evaluation and molecular docking study of novel urea-based benzamide derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.
Guoqing Lu,Wenxing Nie,Meixiu Xin,Ying Meng,Jiayi Gu,Hui Miao,Xinyi Cheng,Albert S. C. Chan,Yong Zou +8 more
TL;DR: In this article , a series of urea-based benzamide derivatives were designed and synthesized based on the structure-based drug design strategy, and the anticancer activities against five human cancer cell lines including HCT116, MDA-MB-231, HeLa, A579 and A375 were evaluated.
Journal ArticleDOI
Differential expression of DNA damage repair genes after chemoradiotherapy and inhibition rate in different bladder cancer cells
TL;DR: In this paper , the authors investigated the potential mechanisms of chemoradiotherapy resistance in patients with bladder cancer, and proposed a new approach to investigate the mechanisms of resistance to the drug.
Journal ArticleDOI
Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy.
Jing Ye,Junhao Wu,Bo Liu +2 more
TL;DR: In this paper , the authors focus on summarizing drug resistance mechanisms of cancer cells, such as enhanced drug efflux, deregulated cell death, DNA damage repair, and epigenetic alterations, and further discuss the current therapeutic strategies of dual-target small molecules to overcome drug resistance.
Posted ContentDOI
Identification of differential polypharmacology between the PARP inhibitor rucaparib and its major metabolite
TL;DR: In this article , the authors used computational and experimental methods to comprehensively characterise the kinase polypharmacology of M324, the major metabolite of the FDA-approved PARP inhibitor rucaparib.
References
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Journal ArticleDOI
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Hannah Farmer,Nuala McCabe,Christopher J. Lord,Andrew Tutt,Andrew Tutt,Damian A. Johnson,Tobias B. Richardson,Manuela Santarosa,Krystyna J. Dillon,Ian Hickson,Charlotte Knights,Niall M. B. Martin,Stephen P. Jackson,Graeme C. M. Smith,Alan Ashworth +14 more
TL;DR: BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis, illustrating how different pathways cooperate to repair damage.
Journal ArticleDOI
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Helen E. Bryant,Nilklas Schultz,Huw D. Thomas,Kayan M. Parker,Dan Flower,Elena Lopez,Suzanne Kyle,Mark Meuth,Nicola J. Curtin,Thomas Helleday,Thomas Helleday +10 more
TL;DR: It is proposed that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair and exploited in order to kill BRCA2-deficient tumours by PARP inhibition alone.
Journal ArticleDOI
Dynamic instability of microtubule growth
TL;DR: It is reported here that microtubules in vitro coexist in growing and shrinking populations which interconvert rather infrequently and this dynamic instability is a general property of micro Tubules and may be fundamental in explaining cellular microtubule organization.
Journal ArticleDOI
The polycomb group protein EZH2 is involved in progression of prostate cancer
Sooryanarayana Varambally,Saravana M. Dhanasekaran,Ming Zhou,Terrence R. Barrette,Chandan Kumar-Sinha,Martin G. Sanda,Debashis Ghosh,Kenneth J. Pienta,Richard George Antonius Bernardus Sewalt,Arie P. Otte,Mark A. Rubin,Arul M. Chinnaiyan +11 more
TL;DR: Dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.
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Microtubule polymerization dynamics
TL;DR: This review describes progress toward understanding the mechanism of dynamic instability of pure tubulin and discusses the function and regulation of microtubule dynamic instability in living cells.
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