Synthesis, biological evaluation and mechanism study of a novel indole-pyridine chalcone derivative as antiproliferative agent against tumor cells through dual targeting tubulin and HK2.

Chalcones have the characteristics of simple structure, easy synthesis and potent anti-tumor activity. Herein, a small library of fifty-five novel indole-chalcone derivatives were rationally designed and facilely synthesized. Consequently, their antiproliferative activity was systematically evaluated.

Human serum albumin promotes interactions between HSA-IL-2 fusion protein and CD122 for enhancing immunotherapy.

Interleukin 2 (IL-2) is a multifunctional cytokine that is crucial for T-lymphocytes proliferation and differentiation. However, IL-2 binds to IL-2Rα (CD25) subunit preferentially and tends to stimulate regulatory T cells (Tregs), which express high-affinity trimeric receptors (IL-2Rαβγ), resulting in immunosuppressive effects. Therefore, development of methods that enhance IL-2/CD122 interactions and activate immune responses without affecting therapeutic efficacy of IL-2 may be desirable.

Design, synthesis and biological evaluation of dual inhibitors targeting AR/AR-Vs and PARP1 in castration resistant prostate cancer therapy.

The combination of androgen signaling inhibitors and PARP inhibitors has shown promising results in clinical trials for the treatment of castration-resistant prostate cancer (CRPC). Multi-target inhibitors can inhibit tumors through different pathways, addressing the limitations of traditional single target inhibitors. We designed and synthesized dual inhibitors targeting AR/AR-Vs and PARP1 using a pharmacophore hybridization strategy.

Sestrin2 plays a protective role in age-related hearing loss by inhibiting NLRP3-inflammasome activity.

Age-related hearing loss (ARHL) is an auditory disease characterized by gradual loss of high-frequency hearing sensitivity. Excessive reactive oxygen species trigger NLRP3-inflammasome activation that may be crucial for ARHL pathogenesis. The antioxidant factor Sestrin2 (SESN2) has been reported to be involved in the remission of oxidative stress and ARHL.

Site-Selective Synthesis of Antitumor C5-Aminated Indoles via Neighboring Aldehyde Group Assisted Catellani Reaction.

A palladium/norbornene (NBE) cooperative catalytic system was developed to access C5-aminated indoles, starting from readily available C4-idonated indoles. Good yields and exclusive site selectivity were achieved for a broad substrate scope, including drug molecule core architectures. Control experiments found that both aldehyde on the C3 position and sulfonyl protecting group on the N1 position were vital for the transformation.

Acriflavine and proflavine hemisulfate as potential antivirals by targeting M.

The evolving SARS-CoV-2 epidemic buffets the world, and the concerted efforts are needed to explore effective drugs. M is an intriguing antiviral target for interfering with viral RNA replication and transcription. In order to get potential anti-SARS-CoV-2 agents, we established an enzymatic assay using a fluorogenic substrate to screen the inhibitors of M.

5-Hydroxymethylcytosine profiles in plasma cell-free DNA reflect molecular characteristics of diabetic kidney disease.

Background: Diabetic kidney disease (DKD), one of the main complications of diabetes mellitus (DM), has become a frequent cause of end-stage renal disease. A clinically convenient, non-invasive approach for monitoring the development of DKD would benefit the overall life quality of patients with DM and contribute to lower medical burdens through promoting preventive interventions.

Methods: We utilized 5hmC-Seal to profile genome-wide 5-hydroxymethylcytosines in plasma cell-free DNA (cfDNA).

The development of New Delhi metallo-β-lactamase-1 inhibitors since 2018.

New Delhi metallo-β-lactamase-1 (NDM-1) can hydrolyze almost all antibiotics of the β-lactam group, resulting in the generation of multidrug resistant bacteria. Besides its broad hydrolytic activity, pathogens expressing NDM-1 often harbor other antibiotic-resistant genes, further promoting the pervasion of multi-resistant clinical isolates and making clinically available drugs scantier. Despite the urgent need for NDM-1 inhibitors, there is no approved drug in clinic.

Proteolysis-targeting chimera molecules targeting SHP2.

SHP2 is a member of the non-receptor protein tyrosine phosphatases, encoded by , and exhibits oncogenic activities. The close association between SHP2 and human cancer has made SHP2 a promising target for clinical therapy. Proteolysis-targeting chimera (PROTAC) technology utilizes the degradation mechanism of the ubiquitin proteasome system to degrade specific proteins.

Ziprasidone suppresses pancreatic adenocarcinoma cell proliferation by targeting GOT1 to trigger glutamine metabolism reprogramming.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant tumor whose effective treatment has not been found. The redox state and proliferative activity of PDAC cells are maintained by the conversion of aspartic acid in the cytoplasm into oxaloacetate though aspartate aminotransferase 1 (GOT1). Therefore, GOT1 inhibitors as a potential approach for treating PDAC have attracted more attention of researchers.

Glutamic oxaloacetic transaminase 1 as a potential target in human cancer.

Glutamic Oxaloacetic Transaminase 1 (GOT1) is one distinct isoenzyme of glutamic oxaloacetic transaminase in eukaryotic cells, which is located in the cytoplasm. To date, several studies have shown that GOT1 plays a critical role in regulating cell proliferation by participating in amino acid metabolism, especially in glutamine metabolism. In addition, GOT1 is overexpressed in many cancer, so GOT1 has been identified as a potentially therapeutic target.

Discovery of linear unnatural peptides as potent mutant isocitrate dehydrogenase 1 inhibitors by Ugi reaction.

Isocitrate dehydrogenases 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to ɑ-ketoglutaric acid (α-KG). It is the most frequently mutated metabolic gene in human cancer and its mutations interfere with cell metabolism and epigenetic regulation, thus promoting tumorigenesis. In order to discover potent new mutant IDH1 inhibitors, based on the structure of marketed inhibitor AG-120 (Ivosidenib), we designed, synthesized and evaluated a series of linear unnatural peptide analogues via Ugi reaction, as potential mutant IDH1 inhibitors.

Preclinical Application of Conditional Reprogramming Culture System for Laryngeal and Hypopharyngeal Carcinoma.

Management of laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) remains highly challenging due to highly variable therapeutic responses. By establishing an model for LHSCC based on conditional reprogramming (CR), a cell-culture technique, we aim to investigate its potential value on personalized cancer therapies. Herein, a panel of 28 human LHSCC CR cells were established from 50 tumor tissues using the CR method.

Chemical Components of the Fruits of Linn.: Methyl Caffeate as a Potential Anticancer Agent by Targeting 3-Phosphoglycerate Dehydrogenase.

Two previously undescribed compounds, moranigrine A () and morusamine (), along with 18 known compounds were isolated from the fruits of Linn. and structurally characterized using spectroscopic data and electronic circular dichroism analyses. All isolates were evaluated for their inhibitory effects on the 3-phosphoglycerate dehydrogenase (PHGDH) enzyme, which catalyzes the first committed step for the synthesis of glucose-derived serine and is associated with many kinds of cancers.

Rational Design and Synthesis of Novel Dual PROTACs for Simultaneous Degradation of EGFR and PARP.

Inspired by the success of dual-targeting drugs, especially bispecific antibodies, we propose to combine the concept of proteolysis targeting chimera (PROTAC) and dual targeting to design and synthesize dual PROTAC molecules with the function of degrading two completely different types of targets simultaneously. A library of novel dual-targeting PROTAC molecules has been rationally designed and prepared. A convergent synthetic strategy has been utilized to achieve high synthetic efficiency.

Withanolides from dietary tomatillo suppress HT1080 cancer cell growth by targeting mutant IDH1.

Isocitrate dehydrogenase (IDH) is one key rate-limiting enzyme in the tricarboxylic acid cycle, which is related to various cancers. Tomatillo (Physalis ixocarpa), a special tomato, is widely consumed as nutritious vegetable in Mexico, USA, etc. As a rich source for withanolides, the fruits of P.

3-Phosphoglycerate dehydrogenase: a potential target for cancer treatment.

Background: Metabolic changes have been recognized as an important hallmark of cancer cells. Cancer cells can promote their own growth and proliferation through metabolic reprogramming. Particularly, serine metabolism has frequently been reported to be dysregulated in tumor cells.

Novel PROTACs for degradation of SHP2 protein.

Protein tyrosine phosphatase SHP2 is a member of PTPs family associated with cancer such as leukemia, non-small cell lung cancer, breast cancer, and so on. SHP2 is a promising target for drug development, and consequently it is of great significance to develop SHP2 inhibitors. Herein, we report CRBN-recruiting PROTAC molecules targeting SHP2 by connecting pomalidomide with SHP099, an allosteric inhibitor of SHP2.

Metal-Protein Nanoparticles Facilitate Anti-VSV and H1N1 Viruses Through the Coordinative Actions on Innate Immune Responses and METTL14.

Host defense systems can invade viral infection through immune responses and cellular metabolism. Recently, many studies have shown that cellular metabolism can be reprogrammed through N -methyladenosine (m A) modifications during viral infection. Among of them, methyltransferase like-14 enzyme (METTL14) plays an important role in m A RNA modification, yet its antiviral function still remains unclear.

Novel selective hexokinase 2 inhibitor Benitrobenrazide blocks cancer cells growth by targeting glycolysis.

Accelerated glucose metabolism is a common feature of cancer cells. Hexokinase 2 (HK2) as the rate-limiting enzyme catalyzes the first step of glucose metabolism. It is overexpressed in most of the human cancers and has been a promising target for cancer therapy.

Furin: A Potential Therapeutic Target for COVID-19.

COVID-19 broke out in the end of December 2019 and is still spreading rapidly, which has been listed as an international concerning public health emergency. We found that the Spike protein of SARS-CoV-2 contains a furin cleavage site, which did not exist in any other betacoronavirus subtype B. Based on a series of analysis, we speculate that the presence of a redundant furin cut site in its Spike protein is responsible for SARS-CoV-2's stronger infectious nature than other coronaviruses, which leads to higher membrane fusion efficiency.