The recent advance and prospect of poly(ADP-ribose) polymerase inhibitors for the treatment of cancer.

Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long-term medication-induced drug resistance. Poly(ADP-ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP-DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first-line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application. However, the intricate mechanisms underlying the drug resistance to PARP inhibitors, including the restoration of homologous recombination, stabilization of DNA replication forks, overexpression of drug efflux protein, and epigenetic modifications pose great challenges and desirability in the development of novel PARP inhibitors. In this review, we will focus on the mechanism, structure-activity relationship, and multidrug resistance associated with the representative PARP inhibitors. Furthermore, we aim to provide insights into the development prospects and emerging trends to offer guidance for the clinical application and inspiration for the development of novel PARP inhibitors and degraders.

New drug approvals for 2022: Synthesis and clinical applications.

The U.S. Food and Drug Administration has approved a total of 37 new drugs in 2022, which are composed of 20 chemical entities and 17 biologics. In particular, 20 chemical entities, including 17 small molecule drugs, 1 radiotherapy, and 2 diagnostic agents, provide privileged scaffolds, breakthrough clinical benefits, and a new mechanism of action for the discovery of more potent clinical candidates. The structure-based drug development with clear targets and fragment-based drug development with privileged scaffolds have always been the important modules in the field of drug discovery, which could easily bypass the patent protection and bring about improved biological activity. Therefore, we summarized the relevant valuable information about clinical application, mechanism of action, and chemical synthesis of 17 newly approved small molecule drugs in 2022. We hope this timely and comprehensive review could bring about creative and elegant inspiration on the synthetic methodologies and mechanism of action for the discovery of new drugs with novel chemical scaffolds and extended clinical indications.

Risk factors of early liver dysfunction after liver transplantation using grafts from donation after citizen death donors.

BACKGROUND: As an early complication after liver transplantation, early allograft dysfunction (EAD) indicates a poor prognosis. This study analyzes the risk factors related to early allograft dysfunction (EAD) after liver transplantation using grafts from donation after citizen death (DCD) to provide a reference for the prevention of EAD after DCD liver transplantation. METHODS: A total of 32 patients who underwent DCD liver transplantation in the organ transplantation center of our hospital from September 2013 to January 2021 were enrolled in this study. The patients were divided into the EAD group and non-EAD group according to whether they developed EAD after transplantation. The general data of the donors and recipients before transplantation, intraoperative conditions, and clinical data within one week after transplantation were compared between the two groups, and related complications were statistically analyzed. The follow-up time was one week postoperatively or, if they died within the first week postoperatively, until the patient died. RESULTS: The subjects included 10 females and 22 males, and the incidence of postoperative EAD was 25% (8/32). Four patients (12%) had primary malignant tumors (primary liver cancer and cholangiocarcinoma), and five donors (15%) had fatty liver. The univariate analysis revealed that the donor BMI (P = 0.005), degree of fatty liver (P = 0.025), aspartate aminotransferase (P = 0.001), alanine aminotransferase (P < 0.001), and total bilirubin (P = 0.009) were related to the occurrence of EAD after DCD liver transplantation. By analyzing the correlation between the incidence EAD and postoperative complications after liver transplantation using grafts from DCD donors, it was shown that the incidence of primary nonfunction (PNF) is related to EAD (P = 0.024). CONCLUSION: Donor BMI, the degree of fatty liver, and preoperative liver function are risk factors for EAD after DCD liver transplantation, and the occurrence of EAD after DCD liver transplantation significantly increases the probability of PNF.