Identifying meaningful drug response biomarkers from public pharmacogenomic datasets with biologically informed interpretable neural networks.

With the advancements of next-generation sequencing, publicly available pharmacogenomic datasets from cancer cell lines provide a handle for developing predictive models of drug responses and identifying associated biomarkers. However, many currently available predictive models are often just used as black boxes, lacking meaningful biological interpretations. In this study, we made use of open-source drug response data from cancer cell lines, in conjunction with KEGG pathway information, to develop sparse neural networks, K-net, enabling the prediction of drug response in EGFR signaling pathways and the identification of key biomarkers.

Identification and structure-activity relationship optimization of dibromoacetophenones as novel mIDH1 inhibitors.

Mutations at arginine 132 in isocitrate dehydrogenase 1 (IDH1) are prevalent in various cancers, making them attractive therapeutic targets. Here, we report the discovery and optimization of a novel dual inhibitor. Initial screening of an in-house library identified lead compound 1-1, which inhibited IDH1 R132H by 73.

Discovery and structure-activity relationship study of novel hydantoin-based inhibitors targeting mutant isocitrate dehydrogenase 1 (mIDH1).

Mutations in isocitrate dehydrogenases (IDHs) are frequently observed in various malignancies. These mutations confer a neomorphic enzymatic activity, leading to the reduction of α-KG to the oncometabolite 2-HG. The aberrant accumulation of 2-HG inhibits α-KG-dependent histone and DNA demethylases, thus contributing to tumorigenesis.

Discovery of thiazolylcyanovinyl benzopyridone acids: Potential new generation antibacterial oxacins?

Here we reported a unique class of new structural thiazolylcyanovinyl benzopyridone acids (TBAs) with large potential to defeat the intractable global bacterial resistance. Some prepared TBAs demonstrated broad-spectrum antibacterial ability, especially ethyl TBA 7b gave low MIC values of 0.25-0.

Self-assembled GSH-responsive polycyclophosphazene loaded honokiol nano-drug for enhanced cancer therapy.

Honokiol (HK), a key bioactive compound extracted from the root and stem bark of Magnolia officinalis, has been a staple in traditional Chinese medicine for over a millennium. Despite its long history of use, HK exhibits low oral bioavailability, which hinders its potential for clinical applications. Herein, we report a GSH-responsive and biodegradable polyphosphazene based Nano-HK particles synthesized via covalent bonding of HK, a disulfide-containing linker, and hexachlorocyclotriphosphazene (HCCP).

Unexpected Discovery of a Novel Triphenylphosphonium Alkylalcohol That Triggers Cancer Cell Death via Mitophagy and Ferroptosis.

Mitochondria-targeted delivery is a promising strategy in anticancer drug development. Triphenylphosphine cation (TPP) is the most widely used mitochondrial-targeting carrier due to the elevated mitochondrial membrane potential (MMP) in cancer cells. Here, we report the serendipitous discovery of a mitochondrial-targeting carrier, compound , which exhibited potent anticancer activity (IC = 70 nM, HCC827) with minimal toxicity to normal cells.

Identification of hydroxyphenyl cyanovinyl thiazoles as new structural scaffold of potential antibacterial agents.

Unique hydroxyphenyl cyanovinyl thiazoles (HCTs) as new structural scaffolds of potential antibacterial agents were developed to overcome global increasingly serious drug resistance. Some synthesized HCTs could suppress the growth of the tested strains, especially, benzothiophenyl HCT 5c exhibited superior anti-Escherichia coli activity with a lower MIC of 0.5 μg/mL to norfloxacin (MIC = 1 μg/mL).

Targeted vancomycin delivery via in situ albumin conjugation and acid-triggered drug release for reduced nephrotoxicity.

Vancomycin has long been considered as the last-resort antibiotic for tacking extremely severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, its clinical application is limited by dose-limiting nephrotoxicity. In this study, we report a novel in situ albumin conjugation and acid sensitive prodrug strategy to selectively release vancomycin at the infection site, thereby minimizing the accumulation of vancomycin in the kidney and thus reducing its nephrotoxicity.

Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation.

KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the in vitro and in vivo efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation.

Synthesis and antibacterial evaluations of novel vancomycin analogues targeting bacteria membrane to combat Gram-negative infections.

Vancomycin is primarily used to treat severe infections caused by Gram-positive bacteria and is often considered as the last-resort therapy in the life-threatening situation. However, it is inherently ineffective against Gram-negative bacteria. Herein, we report the design, synthesis, and biological evaluation of novel vancomycin analogues incorporated with lipophilic cationic groups.

Modular Synthesis of Desferrioxamine B and Its Methotrexate Conjugate as a Selective Trojan Horse Antibiotic That Targets .

A modular synthetic route for desferrioxamine B (DFOB) and its methotrexate (Mtx) conjugate is presented. This route employs acid-sensitive methoxybenzyl groups to protect the hydroxamic acid oxygen, and DFOB was obtained in the 11 longest linear steps with an overall 22% yield. Resulting DFOB-Mtx conjugate exhibits antibacterial activity specifically against with a minimum inhibitory concentration of 3.

Design and Evaluation of Peptide Inhibitors Targeting the Dimerization of SARS-CoV-2 Main Protease.

The severe acute respiratory syndrome virus 2 (SARS-CoV-2) seriously impacted public health. The evolutionarily conserved viral chymotrypsin-like main protease (M) is an important target for anti-SARS-CoV-2 drug development. Previous studies have shown that the eight N-terminal amino acids (N8) of SARS-CoV M are essential for its dimerization, and are used to design inhibitors against SARS-CoV M dimerization.

Protocol for evaluating S-acylated protein membrane affinity using protein-lipid conjugates.

S-acylation of proteins allows their association with membranes. Here, we present a protocol for establishing a platform for membrane affinity evaluation of S-acylated proteins in vitro. We describe steps for preparing lipid-maleimide compounds, mCherry-p62 recombinant proteins, and total cellular membranes.

Synthetic Approaches and Clinical Application of Representative Small-Molecule Inhibitors of Cyclin-Dependent Kinase for Cancer Therapy.

The regulation of the cancer cell cycle heavily relies on cyclin-dependent kinases (CDKs). Targeting CDKs has been identified as a promising approach for effective cancer therapy. In recent years, there has been significant attention paid towards developing small-molecule CDK inhibitors in the field of drug discovery.

Discovery of novel natural-product-derived mutant isocitrate dehydrogenases 1 inhibitors: Structure-based virtual screening, biological evaluation and structure-activity relationship study.

Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes.

Cyanomethylquinolones as a New Class of Potential Multitargeting Broad-Spectrum Antibacterial Agents.

This work identified a class of cyanomethylquinolones (CQs) and their carboxyl analogues as potential multitargeting antibacterial candidates. Most of the prepared compounds showed high antibacterial activities against most of the tested bacteria, exhibiting lower MIC values (0.125-2 μg/mL) than those of clinical norfloxacin, ciprofloxacin, and clinafloxacin.

Novel aminothiazoximone-corbelled ethoxycarbonylpyrimidones with antibiofilm activity to conquer Gram-negative bacteria through potential multitargeting effects.

The emergence of drug-resistant microorganisms threatens human health, and it is usually exacerbated by the formation of biofilm, which forces the development of new antibacterial agents with antibiofilm activity. In this work, a novel category of aminothiazoximone-corbelled ethoxycarbonylpyrimidones (ACEs) was designed and synthesized, and some of the prepared ACEs showed potent bioactivity against the tested bacteria. In particular, imidazolyl ACE 6c showed better inhibitory activity towards Acinetobacter baumannii and Escherichia coli with MIC values both of 0.

Discovery of benzopyridone cyanoacetates as new type of potential broad-spectrum antibacterial candidates.

Unique benzopyridone cyanoacetates (BCs) as new type of promising broad-spectrum antibacterial candidates were discovered with large potential to combat the lethal multidrug-resistant bacterial infections. Many prepared BCs showed broad antibacterial spectrum with low MIC values against the tested strains. Some highly active BCs exhibited rapid sterilization capacity, low resistant trend and good predictive pharmacokinetic properties.

Targeting the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis to discover potent PDK inhibitors through structure-based virtual screening and pharmacological evaluation.

Proliferating cancer cells are characterized by the Warburg effect, a metabolic alteration in which ATP is generated from cytoplasmic glycolysis instead of oxidative phosphorylation. The pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis plays a crucial role in this effect and has been identified as a potential target for anticancer drug development. Herein, we present the discovery and pharmacological evaluation of potent PDK inhibitors targeting the PDK/PDC axis.

Cytosolic malic enzyme and glucose-6-phosphate dehydrogenase modulate redox balance in NSCLC with acquired drug resistance.

Lung cancer cells often show elevated levels of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH). However, the connections between deregulated redox homeostasis in different subtypes of lung cancer and acquired drug resistance in lung cancer have not yet been fully established. Herein, we analyzed different subtypes of lung cancer data reported in the Cancer Cell Line Encyclopedia (CCLE) database, the Cancer Genome Atlas program (TCGA), and the sequencing data obtained from a gefitinib-resistant non-small-cell lung cancer (NSCLC) cell line (H1975GR).

Azolylpyrimidinediols as Novel Structural Scaffolds of DNA-Groove Binders against Intractable .

A unique class of antibacterial azolylpyrimidinediols (APDs) and their analogues were developed. Some synthesized compounds showed excellent bacteriostatic potency; especially, triazolylpyrimidinediol (triazolyl PD) exhibited good anti- potential with a low MIC of 0.002 mmol/L.

Design and synthesis of TPP-Mitomycin C conjugate with reduced toxicity.

Mitomycin C (MMC) is a class of alkylating anticancer drug, which non-specifically interacts with nuclear DNA and cross-links guanine and cytosine of DNA, thereby affecting DNA replication and synthesis. However, toxic effects largely impeded MMC's clinical applications. In this study, triphenylphosphine groups (TPP) were attached to MMC via the active aziridine amine with the aim to reduce its toxicity.