Discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors and efficacy evaluation on a mouse model of liver injury.

Ferroptosis is an iron-dependent regulated cell death, which has been implicated in the onset and progression of numerous diseases. Ferroptosis inhibitors are thought as potential agents for treating these related diseases. However, the majority of currently available ferroptosis inhibitors are antioxidants or iron chelators (called classical ferroptosis inhibitors), which might have potential risks of side effects during clinical use.

Predicting transcriptional responses to novel chemical perturbations using deep generative model for drug discovery.

Understanding transcriptional responses to chemical perturbations is central to drug discovery, but exhaustive experimental screening of disease-compound combinations is unfeasible. To overcome this limitation, here we introduce PRnet, a perturbation-conditioned deep generative model that predicts transcriptional responses to novel chemical perturbations that have never experimentally perturbed at bulk and single-cell levels. Evaluations indicate that PRnet outperforms alternative methods in predicting responses across novel compounds, pathways, and cell lines.

Entropy drives the ligand recognition in G-protein-coupled receptor subtypes.

Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying ligand subtype selectivity, which hampers the rational design of subtype-selective ligands. Herein, we disclose an unusual molecular mechanism of entropy-driven ligand recognition in cannabinoid (CB) receptor subtypes, revealed through atomic-level molecular dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments. This mechanism is attributed to the distinct conformational dynamics of the receptor's orthosteric pocket, leading to variations in ligand binding entropy and consequently, differential binding affinities, which culminate in specific ligand recognition.

Association of systemic inflammatory markers and tertiary lymphoid structure with pathological complete response in gastric cancer patients receiving preoperative treatment: a retrospective cohort study.

Background: Assessment of systemic and local immune responses is crucial in determining the efficacy of cancer interventions. The identification of specific factors that correlate with pathological complete response (pCR) is essential for optimizing treatment decisions.

Methods: In this retrospective study, a total of 521 patients diagnosed with gastric adenocarcinoma who underwent curative gastrectomy following preoperative treatment were reviewed.

From Hit to Lead: Structure-Based Optimization of Novel Selective Inhibitors of Receptor-Interacting Protein Kinase 1 (RIPK1) for the Treatment of Inflammatory Diseases.

Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of cellular necroptosis, which is considered as an important therapeutic target for necroptosis-related indications. Herein, we report the structural optimization and structure-activity relationship investigations of a series of eutectic 5-substituted-indole-3-carboxamide derivatives. The prioritized compound exhibited low nanomolar IC values against RIPK1 and showed good kinase selectivity.

Study of the Effect of Intestinal Microbes on Obesity: A Bibliometric Analysis.

Obesity is a serious public health problem. According to statistics, there are millions of obese people worldwide. Research studies have discovered a complex and intricate relationship between the gut microbiota and obesity.

Discovery of 5-((1H-indazol-3-yl) methylene)-2-thioxoimidazolidin-4-one derivatives as a new class of AHR agonists with anti-psoriasis activity in a mouse model.

Aryl hydrocarbon receptor (AHR) is a ligand dependent transcription factor and participates in the regulation of the immune balance of Th17/22 and Treg cells. It has been found to be widely expressed in the skin, and involved in the pathology of psoriasis. Therefore, AHR is thought as a potential intervention target for psoriasis.

Single-cell RNA sequencing reveals the lineage of malignant epithelial cells and upregulation of TAGLN2 promotes peritoneal metastasis in gastric cancer.

Background: Peritoneal metastasis (PM) is an important factor contributing to poor prognosis in patients with gastric cancer (GC). Transcriptomic sequencing has been used to explore the molecular changes in metastatic cancers, but comparing the bulk RNA-sequencing data between primary tumors and metastases in PM studies is unreasonable due to the small proportion of tumor cells in PM tissues.

Methods: We performed single-cell RNA-sequencing analysis on four gastric adenocarcinoma specimens, including one primary tumor sample (PT), one adjacent nontumoral sample (PN), one peritoneal metastatic sample (MT) and one normal peritoneum sample (MN), from the same patient.

Intraoperative Pathological Evaluation of Suspicious Peritoneal Nodules for Surgical Decision-making in Gastric Cancer.

Background: When frozen pathological results of suspicious peritoneal nodules found in gastric cancer (GC) patients are negative or indeterminant, whether to perform gastrectomy will always be a dilemma for surgeons. This study aimed to facilitate intraoperative surgical decision-making based on frozen section (FS) results and clinicopathological characteristics.

Methods: From January 2015 to July 2021, 318 GC patients were enrolled retrospectively.

Identification of metabolism-related genes for predicting peritoneal metastasis in patients with gastric cancer.

Objective: The reprogramming of metabolism is an important factor in the metastatic process of cancer. In our study, we intended to investigate the predictive value of metabolism-related genes (MRGs) in recurrent gastric cancer (GC) patients with peritoneal metastasis.

Methods: The sequencing data of mRNA of GC patients were obtained from Asian Cancer Research Group (ACRG) and the GEO databases (GSE53276).

Non-classical ferroptosis inhibition by a small molecule targeting PHB2.

Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators.

Generative deep learning enables the discovery of a potent and selective RIPK1 inhibitor.

The retrieval of hit/lead compounds with novel scaffolds during early drug development is an important but challenging task. Various generative models have been proposed to create drug-like molecules. However, the capacity of these generative models to design wet-lab-validated and target-specific molecules with novel scaffolds has hardly been verified.

Tertiary lymphoid structure patterns predicted anti-PD1 therapeutic responses in gastric cancer.

Objective: Recent studies have highlighted the distinct value of tertiary lymphoid structure (TLS) for immunotherapeutic response prediction. However, it remains unclear whether TLS could play such roles in gastric cancer (GC).

Methods: In this study, tumor tissue slices from 292 GC patients from Zhongshan Hospital were firstly reviewed to explore the correlation between TLS and clinical characteristics.

A combination of eye-gaze and head-gaze interactions improves efficiency and user experience in an object positioning task in virtual environments.

Eye-gaze and head-gaze are two hands-free interaction modes in virtual reality, each of which has demonstrated different strengths. Selecting suitable interaction modes in different scenarios is important to achieve efficient interaction in virtual scenes. This study compared the movement time in an object positioning task by examining eye-gaze interaction and head-gaze interaction in various conditions.

An orally available M inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron.

Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (M) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants.

Identification of triazolopyridine derivatives as a new class of AhR agonists and evaluation of anti-psoriasis effect in a mouse model.

The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, can regulate the immune balance of Th17/22 and Treg cells, which plays an important role in the development and maintenance of the skin barrier. We herein report the discovery of triazolopyridine derivatives as a new class of AhR agonists. Structure-activity relationship analyses led to the identification of the most active compound, 6-bromo-2-(4-bromophenyl)-[1,2,4]triazolo[1,5-a]pyridine (12a), with an EC (50% effective concentration) value of 0.

Structural Optimization and Structure-Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6-pyrimido[5,4-][1,4]oxazin-7(8)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants.

Tropomyosin receptor kinases (TrkA, TrkB, and TrkC) are attractive therapeutic targets for multiple cancers. Two first-generation small-molecule Trks inhibitors, larotrectinib and entrectinib, have just been approved to use clinically. However, the drug-resistance mutations of Trks have already emerged, which calls for new-generation Trks inhibitors.

Discovery of 3,4-Dihydrobenzo[][1,4]oxazepin-5(2)-one Derivatives as a New Class of Selective TNIK Inhibitors and Evaluation of Their Anti-Colorectal Cancer Effects.

The Traf2- and Nck-interacting protein kinase (TNIK) is a downstream signal protein of the Wnt/β-catenin pathway and has been thought of as a potential target for the treatment of colorectal cancer (CRC) that is often associated with dysregulation of Wnt/β-catenin signaling pathway. Herein, we report the discovery of a series of 3,4-dihydrobenzo[][1,4]oxazepin-5(2)-one derivatives as a new class of TNIK inhibitors. Structure-activity relationship (SAR) analyses led to the identification of a number of potent TNIK inhibitors with compound being the most active one (IC: 0.

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives.

Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China.

Demethylation of the Promoter Drives Gastric Cancer Progression via the Wnt Pathway.

Wnt signaling is believed to be an important contributor to tumor development and has been reported to be modulated by secreted frizzled-related proteins (SFRP). Nevertheless, the role of secreted frizzled-related protein 4 (SFRP4) in tumorigenesis remains controversial. We aim to explore its biological function in gastric cancer.

Discovery and structure-activity relationship studies of 1-aryl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as potent dual inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and trytophan 2,3-dioxygenase (TDO).

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), which mediate kynurenine pathway of tryptophan degradation, have emerged as potential new targets in immunotherapy for treatment of cancer because of their critical role in immunosuppression in the tumor microenvironment. In this investigation, we report the structural optimization and structure-activity relationship studies of 1-phenyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as a new class of IDO1/TDO dual inhibitors. Among all the obtained dual inhibitors, 1-(3-chloro-4-fluorophenyl)-6-fluoro-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione (38) displayed the most potent IDO1 and TDO inhibitory activities with IC (half-maximal inhibitory concentration) values of 5 nM for IDO1 and 4 nM for TDO.

Discovery of 5-(4-methylpiperazin-1-yl)-2-nitroaniline derivatives as a new class of SIRT6 inhibitors.

SIRT6 is a deacetylase of histone H3 and inhibitors of SIRT6 have been thought as potential agents for treatment of diabetes. Herein we report the discovery of a series of new SIRT6 inhibitors containing the skeleton 1-phenylpiperazine. Among them, compound 5-(4-methylpiperazin-1-yl)-2-nitroaniline (6d) is the most potent one, which showed an IC value of 4.

Discovery of 4-Chromen-4-one Derivatives as a New Class of Selective Rho Kinase (ROCK) Inhibitors, which Showed Potent Activity in ex Vivo Diabetic Retinopathy Models.

Diabetic retinopathy (DR) is a major cause of blindness, and there is a lack of effective treatment at present. Rho-associated coiled-coil containing serine/threonine protein kinases (ROCKs) have recently been suggested as potential targets for the DR treatment. We herein report the discovery of 4-chromen-4-one derivatives as a new class of ROCK inhibitors.