As48, a First-in-Class Dual-Function TREM2 Modulator: Receptor Activation and Shedding Inhibition.

Triggering receptor expressed on myeloid cells 2 (TREM2) dysfunction contributes to Alzheimer's disease pathogenesis, yet current therapeutics cannot prevent ADAM-mediated receptor shedding that diminishes signaling efficacy. Using Affinity Selection-Mass Spectrometry (AS-MS) screening, we identified As48, a novel small molecule that binds TREM2 with high affinity. Biophysical validation confirmed s 7-fold selectivity over TREM1.

An Optimized Enzyme-Coupled Spectrophotometric Method for Measuring Pyruvate Kinase Kinetics.

Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate, producing ATP in the final step of glycolysis. Unlike other isoforms, PKM2 is uniquely regulated, shifting between active tetramers and less active dimers to balance energy production with biosynthetic demands. This flexibility is exploited in cancer cells to support the Warburg effect and anabolic growth.

Phenotypic and targeted drug discovery in immune therapeutics: challenges, opportunities, and future directions.

The development of immune therapeutics has revolutionized modern medicine, particularly in the treatment of cancer and autoimmune diseases. Historically, drug discovery has been guided by two main strategies: phenotypic and target-based approaches. While phenotypic screening has led to the identification of first-in-class therapies, targeted drug discovery has enabled rational drug design based on molecular mechanisms, enhancing precision and therapeutic efficacy.

HTS-Oracle: A Retrainable AI Platform for High-Confidence Hit Identification Across Difficult-to-Drug Targets.

Despite rapid advances in computational drug discovery, high-throughput screening (HTS) remains the primary method for identifying initial hits, particularly for targets with limited tractability to small molecules. Yet conventional HTS campaigns are costly and inefficient, often yielding hit rates below 2% and discarding valuable negative data. Here we present HTS-Oracle, a retrainable, deep learning-based platform that integrates transformer-derived molecular embeddings (ChemBERTa) with classical cheminformatics features in a multi-modal ensemble framework for hit prediction.

Small Molecule-Based Blockade of CD28 Suppresses T Cell Costimulation Across Cellular and Mucosal Co-culture Models.

Background And Purpose: CD28 is a pivotal costimulatory receptor that governs T cell activation through interaction with B7 ligands (CD80/CD86). While antibody-based inhibitors of CD28 signaling have advanced clinically, the development of small molecule modulators remains limited due to the receptor's shallow, flexible surface. We sought to discover small-molecule modulators with favorable pharmacokinetic properties capable of disrupting CD28-B7 interactions in translational models of T cell activation.

Temperature-related intensity change (TRIC)-based high-throughput screening enables the discovery of small molecule CD28 binders.

CD28 is a pivotal costimulatory receptor involved in T cell activation and immune regulation, positioning it as a key therapeutic target for inflammatory diseases, including inflammatory bowel disease (IBD). Despite its potential, small molecules targeting CD28 are still limited. To fill this gap, we developed a high-throughput screening (HTS) platform based on Temperature-Related Intensity Change (TRIC) technology, enabling rapid, immobilization-free screening of chemical libraries of small molecules.

Discovery of CD28-Targeted Small Molecule Inhibitors of T Cell Co-stimulation Using Affinity Selection-Mass Spectrometry (AS-MS) and Ex Vivo Validation.

CD28 is a key T cell co-stimulatory receptor implicated in antitumor immunity and immune-related disorders, yet no small molecule modulators of CD28 have reached clinical development. Here, we report the discovery and characterization of small molecule CD28 antagonists identified through affinity selection-mass spectrometry (AS-MS). Subsequent catalog-based structure-activity relationship (SAR) optimization led to the identification of two lead compounds, 5MS-5 and 19MS-5, which exhibit direct CD28 binding and potent inhibition of CD28-B7 interactions in cellular reporter assays.

Surface Plasmon Resonance (SPR)-Based Workflow for High-Throughput Discovery of CD28-Targeted Small Molecules.

CD28 is a critical costimulatory receptor involved in T cell activation and immune regulation, making it a compelling target for immunomodulatory therapies. Despite its therapeutic relevance, small molecule CD28 inhibitors remain largely underexplored. To address this gap, we developed a high-throughput screening (HTS) workflow using surface plasmon resonance (SPR) to identify novel CD28-targeted small molecules.

CD28 and ICOS in immune regulation: Structural insights and therapeutic targeting.

CD28 and ICOS are key immune checkpoints that regulate T-cell activation, differentiation, and immune tolerance. Their dysregulation contributes to cancer immune evasion, autoimmune diseases, and chronic inflammation, making them critical targets for therapeutic intervention. Recent advances in medicinal chemistry have led to the development of small-molecule inhibitors, monoclonal antibodies, and bispecific antibodies that selectively modulate CD28 and ICOS signaling.

Impact of Cancer-Associated PKM2 Mutations on Enzyme Activity and Allosteric Regulation: Structural and Functional Insights into Metabolic Reprogramming.

Mammalian pyruvate kinase M2 (PKM2) is a key regulator of glycolysis and is highly expressed in proliferative tissues including tumors. Mutations in PKM2 have been identified in various cancers, but their effects on enzyme activity and regulation are not fully understood. This study investigates the structural and functional effects of cancer-associated PKM2 mutations on enzyme kinetics, allosteric regulation, and oligomerization.

Trajectory shaping guidance for impact angle control of planetary hopping robots.

This paper presents a novel optimal trajectory-shaping control concept for a planetary hopping robot. The hopping robot suffers from uncontrolled in-flight and undesired after-landing motions, leading to a position drift at landing. The proposed concept thrives on the Generalized Vector Explicit (GENEX) guidance, which can generate and shape the optimal trajectory and satisfy the end-point constraints like the impact angle of the velocity vector.

Novel prospects in targeting neurodegenerative disorders via autophagy.

Protein aggregation occurs as a consequence of dysfunction in the normal cellular proteostasis, which leads to the accumulation of toxic fibrillar aggregates of certain proteins in the cell. Enhancing the activity of proteolytic pathways may serve as a way of clearing these aggregates in a cell, and consequently, autophagy has surfaced as a promising target for the treatment of neurodegenerative disorders. Several strategies involving small molecule compounds that stimulate autophagic pathway of cell have been discovered.

Exploring the diverse role of pyruvate kinase M2 in cancer: Navigating beyond glycolysis and the Warburg effect.

Pyruvate Kinase M2, a key enzyme in glycolysis, has garnered significant attention in cancer research due to its pivotal role in the metabolic reprogramming of cancer cells. Originally identified for its association with the Warburg effect, PKM2 has emerged as a multifaceted player in cancer biology. The functioning of PKM2 is intricately regulated at multiple levels, including controlling the gene expression via various transcription factors and non-coding RNAs, as well as adding post-translational modifications that confer distinct functions to the protein.

Structural and mechanistic insights into ALS patient derived mutations in D-amino acid oxidase.

The D-amino acid oxidase protein modulates neurotransmission by controlling the levels of D-serine, a co-agonist of N-methyl-D-aspartate receptors. Mutations in the DAO gene have been associated with ALS, with some studies reporting pathogenic mechanisms of the R199W mutation. We have characterized two novel mutations R38H and Q201R found in ALS patients and report certain novel findings related to the R199W mutation.