Discovery of Novel 5-Cyano-3-phenylindole-Based LSD1/HDAC Dual Inhibitors for Colorectal Cancer Treatment.

The dual inhibition of histone lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) has emerged as a promising strategy for cancer therapy. In this study, we report the discovery of novel 5-cyano-3-phenylindole-based LSD1/HDAC dual inhibitors, evaluated through both in vitro and in vivo assays. Among these inhibitors, compound was identified as particularly potent, exhibiting high inhibitory activity against LSD1 (IC = 39.

Cell-Based Screen Identifies a Highly Potent and Orally Available ABCB1 Modulator for Treatment of Multidrug Resistance.

Targeting ABCB1 is a promising strategy in combating multidrug resistance. Our cell-based phenotypic screening led to the discovery of novel triazolo[1,5-]pyrimidone-based ABCB1 modulators. Notably, was identified as a significant contributor to heightened sensitization of human colorectal adenocarcinoma cells (SW620/Ad300) to paclitaxel (IC = 5 nM).

Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer.

LSD1 (histone lysine-specific demethylase 1) has been gradually disclosed to act as an immunomodulator to enhance antitumor immune response. Despite the identification of numerous potent LSD1 inhibitors, there remains a lack of LSD1 inhibitors approved for marketing. Novel LSD1 inhibitors with different mechanisms are therefore needed.

Roles and inhibitors of FAK in cancer: current advances and future directions.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase-independent pathways. Moreover, FAK is crucial for sustaining the tumor microenvironment.

HER2 advanced gastric cancer: Current state and opportunities (Review).

Human epidermal growth factor receptor 2 (HER2) gastric cancer (GC) is a distinct subtype of GC, accounting for 10‑20% of all cases of GC. Although the development of the anti‑HER2 monoclonal antibody trastuzumab has markedly improved response rates and prognosis of patients with HER2 advanced GC (AGC), drug resistance remains a considerable challenge. Therefore, dynamic monitoring of HER2 expression levels can facilitate the identification of patients who may benefit from targeted therapy.

Degraders in epigenetic therapy: PROTACs and beyond.

Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance.

Synthesis and clinical application of new drugs approved by FDA in 2022.

The pharmaceutical industry had a glorious year in 2022, with a total of 37 new drugs including 20 new chemical entities (NCEs) and 17 new biological entities (NBEs) approved by the Food and Drug Administration (FDA). These drugs are mainly concentrated in oncology, central nervous system, antiinfection, hematology, cardiomyopathy, dermatology, digestive system, ophthalmology, MRI enhancer and other therapeutic fields. Of the 37 drugs, 25 (68%) were approved through an expedited review pathway, and 19 (51%) were approved to treat rare diseases.

The recent advance of Interleukin-1 receptor associated kinase 4 inhibitors for the treatment of inflammation and related diseases.

The interleukin-1 receptor associated kinase 4 (IRAK-4) is a member of serine-threonine kinase family, which plays an important role in the regulation of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs) related signaling pathways. At present, the IRAK-4 mediated inflammation and related signaling pathways contribute to inflammation, which are also responsible for other autoimmune diseases and drug resistance in cancers. Therefore, targeting IRAK-4 to develop single-target, multi-target inhibitors and proteolysis-targeting chimera (PROTAC) degraders is an important direction for the treatment of inflammation and related diseases.

Oxazolidinone: A promising scaffold for the development of antibacterial drugs.

Due to the long-term and widespread use of antibiotics in clinic, the problem of bacterial resistance is increasingly serious, and the development of new drugs to treat drug-resistant bacteria has gradually become the mainstream direction of antibiotic research. The oxazolidinone-containing drugs linezolid, tedizolid phosphate and contezolid have been approved to the market, which are effective against a variety of Gram-positive bacterium infections. Moreover, there are also many antibiotics containing oxazolidinone fragment under clinical investigation that show good pharmacokinetic and pharmacodynamic properties with unique mechanism of action against resistant bacteria.

Preclinical studies of the triazolo[1,5-]pyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor.

Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-]pyrimidine-based compound as a highly potent, specific, and orally active P-gp inhibitor.

Discovery of the Triazolo[1,5-]Pyrimidine-Based Derivative WS-898 as a Highly Efficacious and Orally Bioavailable ABCB1 Inhibitor Capable of Overcoming Multidrug Resistance.

Targeting P-glycoprotein (ABCB1 or P-gp) has been recognized as a promising strategy to overcome multidrug resistance. Here, we reported our medicinal chemistry efforts that led to the discovery of the triazolo[1,5-]pyrimidine derivative as a highly effective ABCB1 inhibitor capable of reversing paclitaxel (PTX) resistance in drug-resistant SW620/Ad300, KB-C2, and HEK293/ABCB1 cells (IC = 5.0, 3.

Discovery of a cinnamyl piperidine derivative as new neddylation inhibitor for gastric cancer treatment.

Targeting neddylation pathway has been recognized as an attractive anticancer therapeutic strategy, thus discovering potent and selective neddylation inhibitors is highly desirable. Our work reported the discovery of novel cinnamyl piperidine compounds and their antitumor activity in vitro and in vivo. Among these compounds, compound 4g was identified as a novel neddylation inhibitor and decreased the neddylation levels of cullin 1, cullin 3 and cullin 5.

Overview on the Role of E-Cadherin in Gastric Cancer: Dysregulation and Clinical Implications.

Gastric cancer is the fifth most common cancer and the third most common cause of cancer death all over the world. E-cadherin encoded by human gene plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. Full-length E-cadhrin tethered on the cell membrane mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues.

FDA-approved pyrimidine-fused bicyclic heterocycles for cancer therapy: Synthesis and clinical application.

Considerable progress has been made in the development of anticancer agents over the past few decades, and a lot of new anticancer agents from natural and synthetic sources have been produced. Among heterocyclic compounds, pyrimidine-fused bicyclic heterocycles possess a variety of biological activities such as anticancer, antiviral, etc. To date, 147 pyrimidine-fused bicyclic heterocycles have been approved for clinical assessment or are currently being used in clinic, 57 of which have been approved by FDA for clinical treatment of various diseases, and 22 of them are being used in the clinic for the treatment of different cancers.

Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer.

Kremen2 (Krm2) plays an important role in embryonic development, bone formation, and tumorigenesis as a crucial regulator of classical Wnt/-catenin signaling pathway. However, the role of Krm2 in gastric cancer is not clear. The aim of this study was to explore the regulatory role of Krm2 in the tumorigenesis and metastasis of gastric cancer.

EBV-Positive Gastric Cancer: Current Knowledge and Future Perspectives.

Gastric cancer is the fifth most common malignant tumor and second leading cause of cancer-related deaths worldwide. With the improved understanding of gastric cancer, a subset of gastric cancer patients infected with Epstein-Barr virus (EBV) has been identified. EBV-positive gastric cancer is a type of tumor with unique genomic aberrations, significant clinicopathological features, and a good prognosis.

Structure-Based Design, Synthesis, and Biological Evaluation of New Triazolo[1,5-]Pyrimidine Derivatives as Highly Potent and Orally Active ABCB1 Modulators.

ABCB1 is a promising therapeutic target for overcoming multidrug resistance (MDR). In this work, we reported the structure-based design of triazolo[1,5-]pyrimidines as new ABCB1 modulators, of which significantly increased sensitization of ABCB1-overexpressed SW620/Ad300 cells to paclitaxel (PTX) (IC = 22.02 nM).

Steroidal dimer by001 inhibits proliferation and migration of esophageal cancer cells via multiple mechanisms.

Objective: To investigate the potential inhibitory effects of structurally novel steroidal dimer by001 in esophageal cancer in vitro.

Methods: The cytotoxicity of by001 on esophageal, gastric, neuroblastoma and prostate cancer cells was examined MTT assay and colony formation assay. By001 induced apoptosis and production of intracellular reactive oxygen species on esophageal cancer cells Ec109, TE-1 and human normal gastric epithelial cells GES-1 was detected by flow cytometry.

Discovery of a non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) that modulates ABCB1-mediated multidrug resistance (MDR).

Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied.

Discovery of a non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) that modulates ABCB1-mediated multidrug resistance (MDR).

Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied.

Geridonin, a novel derivative of oridonin, inhibits proliferation of MGC 803 cells both in vitro and in vivo through elevating the intracellular ROS.

Objectives: To study the antitumour activity of a novel derivative of oridonin named geridonin in vitro and in vivo.

Methods: MTT and colony formation assay were used to test the cytotoxicity of geridonin; apoptosis, cell cycle arrest and the levels of reactive oxygen species were measured by flow cytometry; JC-1 staining assay was used to examine the mitochondrial membrane potential; the MGC 803 xenograft model was established to evaluate the antitumour effect of geridonin in vivo; H&E staining was performed for the histological analysis.

Key Findings: In vitro, geridonin remarkably inhibited proliferation of gastrointestinal cancer cells including oesophageal, gastric, liver and colon cancers.

Geridonin and paclitaxel act synergistically to inhibit the proliferation of gastric cancer cells through ROS-mediated regulation of the PTEN/PI3K/Akt pathway.

Paclitaxel, a taxane, is a cytotoxic chemotherapeutic agent that targets microtubules. It has become a front-line therapy for a broad range of malignancies, including lung, breast, gastric, esophageal, and bladder carcinomas. Although paclitaxel can inhibit tumor development and improve survival, poor solubility, myelotoxicity, allergic reactions, and drug resistance have restricted its clinical application.

Design and synthesis of isatin/triazole conjugates that induce apoptosis and inhibit migration of MGC-803 cells.

A series of new isatin/triazole conjugates were designed based on the hypothesis that the ester-linked compounds could be enzymatically hydrolyzed by cellular esterases inside the cells. These compounds showed moderate to good growth inhibition toward the tested cancer cells, exerted selective inhibition toward MGC-803 cells and were less toxic to normal cells HL-7702 and GES-1. Of these compounds, compound 5a showed the best inhibitory activity against MGC-803 cells (IC = 9.

Design and synthesis of novel 1,2,3-triazole-pyrimidine-urea hybrids as potential anticancer agents.

A series of novel 1,2,3-triazole-pyrimidine-urea hybrids were designed, synthesized and evaluated for anticancer activity against four selected cancer cell lines (MGC-803, EC-109, MCF-7 and B16-F10). Majority of the synthesized compounds exhibited moderate to potent activity against all the cancer cell lines assayed. Particularly, compounds 26, 30 and 38 exhibited excellent growth inhibition against B16-F10 with IC50 values of 32nM, 35nM and 42nM, respectively.