Development and therapeutic potential of DNA-dependent protein kinase inhibitors.

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.

Discovery of plant-derived anti-tumor natural products: Potential leads for anti-tumor drug discovery.

Natural products represent a paramount source of novel drugs. Numerous plant-derived natural products have demonstrated potent anti-tumor properties, thereby garnering considerable interest in their potential as anti-tumor drugs. This review compiles an overview of 242 recently discovered natural products, spanning the period from 2018 to the present. These natural products, which include 69 terpenoids, 42 alkaloids, 39 flavonoids, 21 steroids, 14 phenylpropanoids, 5 quinolines and 52 other compounds, are characterized by their respective chemical structures, anti-tumor activities, and mechanisms of action. By providing an essential reference and fresh insights, this review aims to support and inspire researchers engaged in the fields of natural products and anti-tumor drug discovery.

Prevention and Potential Treatment Strategies for Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is a significant viral pathogen that causes respiratory infections in infants, the elderly, and immunocompromised individuals. RSV-related illnesses impose a substantial economic burden worldwide annually. The molecular structure, function, and in vivo interaction mechanisms of RSV have received more comprehensive attention in recent times, and significant progress has been made in developing inhibitors targeting various stages of the RSV replication cycle. These include fusion inhibitors, RSV polymerase inhibitors, and nucleoprotein inhibitors, as well as FDA-approved RSV prophylactic drugs palivizumab and nirsevimab. The research community is hopeful that these developments might provide easier access to knowledge and might spark new ideas for research programs.

Design, synthesis and biological evaluation of novel 1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-based AAK1 inhibitors with anti-viral property against SARS-CoV-2.

Coronavirus entry into host cells hinges on the interaction between the spike glycoprotein of the virus and the cell-surface receptor angiotensin-converting enzyme 2 (ACE2), initiating the subsequent clathrin-mediated endocytosis (CME) pathway. AP-2-associated protein kinase 1 (AAK1) holds a pivotal role in this pathway, regulating CME by modulating the phosphorylation of the µ subunit of adaptor protein 2 (AP2M1). Herein, we report a series of novel AAK1 inhibitors based on previously reported 1,2,4a,5-tetrahydro-4H-benzo[b] [1,4]oxazino[4,3-d] [1,4]oxazine scaffold. Among 23 synthesized compounds, compound 12e is the most potent one with an IC50 value of 9.38 ± 0.34 nM against AAK1. The in vitro antiviral activity of 12e against SARS-CoV-2 was evaluated using a model involving SARS-CoV-2 pseudovirus infecting hACE2-HEK293 host cells. The results revealed that 12e was superior in vitro antiviral activity against SARS-CoV-2 entry into host cells when compared to SGC-AAK1-1 and LX9211, and its activity was comparable to that of a related and reference compound 8. Mechanistically, all AAK1 inhibitors attenuated AAK1-induced phosphorylation of AP2M1 threonine 156 and disrupted the direct interaction between AP2M1 and ACE2, ultimately inhibiting SARS-CoV-2 infection. Notably, compounds 8 and 12e exhibited a more potent effect in suppressing the phosphorylation of AP2M1 T156 and the interaction between AP2M1 and ACE2. In conclusion, novel AAK1 inhibitor 12e demonstrates significant efficacy in suppressing SARS-CoV-2 infection, and holds promise as a potential candidate for developing novel antiviral drugs against SARS-CoV-2 and other coronavirus infections.

Design, Synthesis, and Structure-Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition.

Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. To elucidate whether simultaneous inhibition of these two targets could interfere with these two signal pathways, a series of pyridazinone-based PARP7/HDACs dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between anticancer immunity and HDAC inhibition.

Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment.

Bifunctional conjugates targeting PD-L1/PARP7 were designed, synthesized, and evaluated for the first time. Compounds B3 and C6 showed potent activity against PD-1/PD-L1 interaction (IC50 = 0.426 and 0.342 µM, respectively) and PARP7 (IC50 = 2.50 and 7.05 nM, respectively). They also displayed excellent binding affinity with hPD-L1, approximately 100-200-fold better than that of hPD-1. Both compounds restored T-cell function, leading to the increase of IFN-γ secretion. In the coculture assay, B3 and C6 enhanced the killing activity of MDA-MB-231 cells by Jurkat T cells in a concentration-dependent manner. Furthermore, B3 and C6 displayed significant in vivo antitumor efficacy in a melanoma B16-F10 tumor mouse model, more than 5.3-fold better than BMS-1 (a PD-L1 inhibitor) and RBN-2397 (a PARP7i clinical candidate) at the dose of 25 mg/kg, without observable side effects. These results provide valuable insight and understanding for developing bifunctional conjugates for potential anticancer therapy.

Determining optimal ALT cut-off values for predicting significant hepatic histological changes in patients with normal ALT in the grey zone of chronic hepatitis B virus infection.

BACKGROUND AND AIMS: We aimed to define gender-specific, optimal alanine aminotransferase (ALT) cut-off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT. METHODS: In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut-off values. Area under the curve (AUC) values were calculated to assess their predictive performance. RESULTS: A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut-off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut-off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut-off values were greater than those of the current recommendations. CONCLUSION: This study established novel optimal ALT cut-off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy.