AuNP aggregation-triggered conformational changes in hairpin probes for dual-mode colorimetric and SERS detection of TTX.

Tetrodotoxin (TTX) is a potent neurotoxic marine biotoxin that poses severe health risks. To address this challenge, a dual-mode detection strategy was developed based on TTX-induced conformational changes in hairpin probes (HP), regulation of Au NPs aggregation to modulate localized surface plasmon resonance, and hotspot formation for colorimetric and surface-enhanced Raman spectroscopy (SERS) signal detection. This method demonstrates higher specificity than ion-induced aggregation.

A novel surface-enhanced raman scattering strategy integrating spectral and mapping data for stable and rapid detection of aflatoxin B1 via supervised learning.

Surface-enhanced Raman scattering (SERS) holds great potential for aflatoxin B1 (AFB1) monitoring, but its reliability is hampered by inconsistent hotspot uniformity and signal fluctuations from single-spot measurements. To overcome these limitations, this study proposed a strategy combining substrates with high hotspot uniformity and multi-dimensional data fusion to enhance detection stability. Three-dimensional (3D) gold nanotrees were fabricated via electrodeposition, which served as SERS substrates for mapping signal generation.

Discovery of a first-in-class PROTAC degrader of histone lysine demethylase KDM4.

Targeting histone lysine demethylase 4 (KDM4) has emerged as a promising approach for cancer therapy. Despite significant progress in developing KDM4 inhibitors, many of these compounds demonstrate poor selectivity or limited cellular efficacy, and none have received approval for marketing. In this study, we designed and synthesized a series of novel KDM4-targeted proteolysis targeting chimeras (PROTAC) degraders, as exemplified by compound 11 (RDN8011).

Design, synthesis and evaluation of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives as next generation selective RET inhibitors overcoming RET solvent front mutations (G810C/R).

RET is a well-recognized drug target for cancer treatment. Despite the promising efficacy of selective second-generation RET inhibitors Selpercatinib and Pralsetinib, the clinical benefits have been compromised due to the quickly developed resistance to these drugs. RET G810 mutations at the solvent front site have been identified as the major on-target mutations contributing to resistance against Selpercatinib and Pralsetinib.

Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations.

Rearranged during transfection (RET) kinase is a validated therapeutic target for various cancers characterized by RET alterations. Although two selective RET inhibitors, selpercatinib and pralsetinib, have been approved by the FDA, acquired resistance through solvent-front mutations has been identified rapidly. Developing proteolysis targeting chimera (PROTAC) targeting RET mutations offers a promising strategy to combat drug resistance.

AFB1-responsive mesoporous silica nanoparticles for AFB1 quantification based on aptamer-regulated release of SERS reporter.

In this study, we propose a novel surface-enhanced Raman scattering (SERS) method for quantifying aflatoxin B1 (AFB1). This method relies on the target-triggered release of a SERS reporter from aptamer-sealed aminated mesoporous silica nanoparticles (MSNs). These MSNs were synthesized to accommodate 4-mercaptophenylboronic acid (4-MPBA) within their well-defined micropores, which were subsequently sealed with AFB1 aptamers.

A three-channel biosensor based on stimuli-responsive catalytic activity of the FeO@Cu for on-site detection of tetrodotoxin in fish.

Tetrodotoxin (TTX), a lethal neurotoxin, poses a grave threat to human health. The available spectroscopic methods suffer from limitations such as complex procedures and inadequate on-site capabilities. In this study, we proposed a method using FeO@Cu as a catalytic biosensor combined with SERS, colorimetry and image processing for TTX detection.

Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy.

Glutathione peroxidase 4 (GPX4) emerges as a promising target for the treatment of therapy-resistant cancer through ferroptosis. Thus, there is a broad interest in the development of GPX4 inhibitors. However, a majority of reported GPX4 inhibitors utilize chloroacetamide as a reactive electrophilic warhead, and the selectivity and pharmacokinetic properties still need to be improved.

Discovery of 3,5-diaryl-1H-pyrazol-based ureas as potent RET inhibitors.

Rearranged during transfection (RET) is a promising target for antitumor drug development. Multikinase inhibitors (MKI) have been developed for RET-driven cancers but displayed limited efficacy in disease control. Two selective RET inhibitors were approved by FDA in 2020 and proved potent clinical efficacy.

Comparison of Different Competitive Proteome Profiling Approaches in Target Identification of Covalent Inhibitors.

Competitive proteome profiling is a powerful approach for the identification of targets of small molecules. This approach usually employs an inhibitor-derived probe or a cysteine-reactive probe such as an IA-alkyne in a comparison between inhibitor-treated and untreated samples, thus enabling distinction between genuine targets and nonspecific labeling. We have developed an active probe derived from an EGFR inhibitor, afatinib, and a cysteine reactive probe, an alkyne-containing α,β-unsaturated amide, to compare their characterization of cellular targets.

Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells.

The combination of histone deacetylase inhibitor and BRAF inhibitor (BRAFi) has been shown to enhance the antineoplastic effect and reduce the progress of BRAFi resistance. In this study, a series of (thiazol-5-yl)pyrimidin-2-yl)amino)--hydroxyalkanamide derivatives were designed and synthesized as novel dual inhibitors of BRAF and HDACs using a pharmacophore hybrid strategy. In particular, compound possessed potent activities against BRAF, HDAC1, and HDAC6 enzymes.

Discovery of JND003 as a New Selective Estrogen-Related Receptor α Agonist Alleviating Nonalcoholic Fatty Liver Disease and Insulin Resistance.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver diseases and is causally linked to hepatic insulin resistance and reduced fatty acid oxidation. Therapeutic treatments targeting both hepatic insulin resistance and lipid oxidative metabolism are considered as feasible strategies to alleviate this disease. Emerging evidence suggests Estrogen-Related Receptor alpha (ERRα), the first orphan nuclear receptor identified, as a master regulator in energy homeostasis by controlling glucose and lipid metabolism.

Discovery of Hexahydrofuro[3,2-]furans as New Kinase-Selective and Orally Bioavailable JAK3 Inhibitors for the Treatment of Leukemia Harboring a JAK3 Activating Mutant.

Janus kinase 3 (JAK3) is a potential target for the treatment of hematological malignancies. Herein, we report the discovery of a series of new orally bioavailable irreversible JAK3 kinase inhibitors. The representative compound potently inhibited JAK3 kinase activity with an IC value of 1.

Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR Mutants.

A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR inhibitors. One of the most potent and selective compounds strongly suppressed the EGFR and EGFR kinases with IC values of 0.7 and 3.

Design, Synthesis, and Biological Evaluation of 2-Formyl Tetrahydronaphthyridine Urea Derivatives as New Selective Covalently Reversible FGFR4 Inhibitors.

Aberrant FGF19/FGFR4 signaling is an oncogenic driver force for the development of human hepatocellular carcinoma (HCC). A series of 2-formyl tetrahydronaphthyridine urea derivatives were designed and synthesized as new covalently reversible inhibitors of FGFR4. The representative compound exhibited an IC value of 5.

Research on the Early-Warning Model of Network Public Opinion of Major Emergencies.

The rapid development of Internet in recent years has led to a proliferation of social media networks as people who can gather online to share information, knowledge, and opinions. However, the network public opinion tends to generate strongly misleading and a large number of messages can cause shocks to the public once major emergencies appear. Therefore, we need to make correct prediction regarding and timely identify a potential crisis in the early warning of network public opinion.

Development and application of novel electrophilic warheads in target identification and drug discovery.

Nucleophilic amino acids play important roles in maintenance of protein structure and function, covalent modification of such amino acid residues by therapeutic agents is an efficient way to treat human diseases. Most of current clinical drugs are structurally limited to α,β-unsaturated amide as an electrophilic warhead. To alleviate this issue, many novel electrophiles have been developed in recent years that can covalently bind to different amino acid residues and provides a unique way to interrogate proteins, including "undruggable" targets.

Identification of New Small-Molecule Inducers of Estrogen-related Receptor α (ERRα) Degradation.

A series of ()-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxyphenyl)-2-cyanoacrylamide derivatives were designed and synthesized as new estrogen-related receptor α (ERRα) degraders based on the proteolysis targeting chimera (PROTAC) concept. One of the representative compounds is capable of specifically degrading ERRα protein by >80% at a relatively low concentration of 30 nM, becoming one of the most potent and selective ERRα degraders to date. Compound could be utilized as a new powerful research tool for further biological investigation of ERRα.

Stereoselective synthesis of enamino ketones through an aza-Michael/hydrolysis cascade reaction.

We have developed a mild, convenient and efficient synthesis of highly functionalized (Z)-β-enamino ketones from readily available 3,4-dihydroisoquinoline imines and ynones through an aza-Michael/hydrolysis cascade reaction. This method is also suitable for the preparation of (Z)-β-enamino esters using alkynoates as starting materials. Complex fully substituted pyrroles can be constructed from the obtained (Z)-β-enamino ketones.

4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New Axl Kinase Inhibitors.

Axl is a new potential target for anticancer drug discovery. A series of 4-oxo-1,4-dihydroquinoline-3-carboxamides were designed and synthesized as highly potent Axl kinase inhibitors. One of the most promising compounds, 9im, tightly bound with Axl protein and potently inhibited its kinase function with a Kd value of 2.

Recent advance in the design of small molecular modulators of estrogen-related receptors.

The estrogen-related receptors (ERRs), comprising ERRα, ERRβ and ERRγ, are the members of the nuclear receptor superfamily, which have been functionally implicated in estrogen signal pathway in various patterns. However, no natural ligand of ERRs has been identified to data, so identification of the synthetic modulators (inverse agonist and agonist) of ERRs would be highly effective in the treatment of estrogen-related pathologies, such as diabetes, breast cancer and osteoporosis. This review summarizes the structures and biological functions of ERR subtypes, and the progress in designing the small molecular modulators of ERRs as well as the detailed description of available co-crystal structures of the LBD of ERRs in three distinct states: unligand, inverse agonist bound, and agonist bound.

Identification of pyrido[1,2-α]pyrimidine-4-ones as new molecules improving the transcriptional functions of estrogen-related receptor α.

The nuclear estrogen-related receptor α (ERRα) plays a central role in the regulation of expression of the genes involved in mitochondrial biogenesis and oxidative metabolism. We have successfully identified a series of pyrido[1,2-a]pyrimidin-4-ones as new agonists enhancing the transcriptional functions of ERRα. The compounds potently elevated the mRNA levels and the protein levels of ERRα downstream targets.

Structure-activity study on a series of α-glutamic acid scaffold based compounds as new ADAMTS inhibitors.

A series of α-glutamic acid scaffold based 4-(benzamido)-4-(1,3,4-oxadiazol-2-yl) butanoic acids were designed and synthesized as new ADAMTS inhibitors. The compounds dose-dependently inhibited the enzymatic activities of ADAMTS-4 and ADAMTS-5. One of the most active compound 2h potently inhibited ADAMTS-4 and ADAMTS-5 with IC(50) values of 1.