The process of poly(ADP-ribosyl)ation and the major enzyme that catalyses this reaction, poly(ADP-ribose) polymerase 1 (PARP1), were discovered more than 50 years ago. Since then, advances in our understanding of the roles of PARP1 in cellular processes such as DNA repair, gene transcription and cell death have allowed the investigation of therapeutic PARP inhibition for a variety of diseases — particularly cancers in which defects in DNA repair pathways make tumour cells highly sensitive to the inhibition of PARP activity. Efforts to identify and evaluate potent PARP inhibitors have so far led to the regulatory approval of four PARP inhibitors for the treatment of several types of cancer, and PARP inhibitors have also shown therapeutic potential in treating non-oncological diseases. This Review provides a timeline of PARP biology and medicinal chemistry, summarizes the pathophysiological processes in which PARP plays a role and highlights key opportunities and challenges in the field, such as counteracting PARP inhibitor resistance during cancer therapy and repurposing PARP inhibitors for the treatment of non-oncological diseases. Several poly(ADP-ribose) polymerase (PARP) inhibitors have now been approved as treatments for various types of cancer. In this Review, Curtin and Szabo discuss the history of the development of PARP inhibitors and progress in their use for cancer therapy, as well as the potential for repurposing PARP inhibitors for the treatment of non-oncological diseases such as stroke.

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Poly(ADP-ribose) polymerase inhibition: past, present and future

Fuzuloparib (AiRuiYi®, ; formerly fluzoparib) is a small molecule, orally active PARP inhibitor being developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. (formerly Jiangsu Hengrui Medicine Co., Ltd.) for the treatment of solid cancers. Fuzuloparib has been approved in China for the treatment of ovarian cancer (including fallopian tube cancer or primary peritoneal cancer), and phase II and III trials are investigating fuzuloparib for the treatment of other solid cancers, including cancers of the pancreas, breast, prostate and lungs. This article summarizes the milestones in the development of fuzuloparib leading to this first approval for the treatment of platinum-sensitive recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer in patients with germline BRCA mutation who have undergone second-line or above chemotherapy.

/pdf/fuzuloparib-first-approval-3mz8t0r2fo.pdf

Fuzuloparib: First Approval.

Discovery of small molecules that impede the activity of single-strand DNA repair enzyme, PARP1, has led to four marketed drugs for the treatment of advanced-stage cancers. Hence, there is a renewe...

Recent development in the discovery of PARP inhibitors as anticancer agents: a patent update (2016-2020)

Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers.

We report a rare case of 62-year-old South Asian women who visited the Molecular Pathology and Genomics Department for hereditary germline cancer genetic testing after being diagnosed with oesophageal cancer, reported as invasive keratinizing squamous cell carcinoma metastasized to the lymph nodes. Her personal history revealed that she was diagnosed with triple-negative breast cancer five years before oesophageal cancer. Germline cancer testing showed pathogenic variants in BRCA1 gene c.68_69delAG, which proved it a hereditary breast and ovarian cancer syndrome. She was started on PARP inhibitors but developed some secondary respiratory failure and succumbed to death. Less than 10 cases have been reported in the literature of the association of germline BRCA1 and Squamous cell Carcinoma – the esophagus. The article focuses on the probable pathogenesis of BRCA1 mutation with non-classic malignancies and the response of Poly adenosine diphosphate ribose polymerase inhibitors (PARP) inhibitors in such a scenario. We report an unusual manifestation of the BRCA1 gene with second primary oesophageal squamous cell cancer occurring five years later to triple-negative breast cancer. 

Germline BRCA1 Mutation inSquamous Cell Carcinoma of Oesophagus: Driver versus Passenger Mutation

4060Background: Fluzoparib (SHR3162) is an oral, selective PARP1 inhibitor. In our gastric cancer PDX model, fluzoparib + apatinib + paclitaxel demonstrated significant tumor growth inhibition as c...

Phase I study of fluzoparib, a PARP1 Inhibitor in combination with apatinib and paclitaxel in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.

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Phase I study of fluzoparib, a PARP1 Inhibitor in combination with apatinib and paclitaxel in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.