Papers & Updates

This study employed a structure-based virtual screening approach to repurpose FDA-approved drugs for targeting druggable hot spots on the previously "undruggable" β-catenin/Tcf4 protein-protein interaction, a key driver in colorectal cancer. Computational analysis identified Leucovorin, Carbenicillin, and Ceforanide as promising binders. Experimental validation in colorectal cancer cells confirmed that Carbenicillin and Ceforanide significantly reduced cell viability and proliferation, demonstrating the feasibility of targeting this interaction with small molecules and suggesting them as repurposed therapeutic candidates.

This study addressed the challenge of achieving selectivity in MMP-9 inhibitors by employing an in silico fragment-based drug design (FBDD) workflow targeting its non-conserved S1' pocket. Through virtual screening, fragment growing, docking, and molecular dynamics simulations, the researchers identified optimized small molecules that demonstrated enhanced binding affinity and preferential selectivity for MMP-9 over other isoforms in silico, establishing a promising framework for selective inhibitor development.

This review systematically surveys recent advances in dual PROTACs, which overcome limitations of single-target degraders by simultaneously eliminating two or more pathogenic proteins for complex diseases. It critically analyzes design strategies, SAR, and E3 ligase selection across degraders targeting homologous and distinct protein pairs. Despite significant progress, including novel dual degraders for epigenetic regulators and protein aggregates, challenges in pharmacokinetics, off-target toxicity, and E3 ligase diversity persist.

Analyzing data from a Phase 1/1b trial of the B7H3 ADC YL201, researchers found that a high baseline neutrophil-to-lymphocyte ratio (NLR) was associated with inferior treatment response and progression-free survival, particularly in NSCLC patients. High baseline NLR also correlated with a distinct toxicity profile (increased thrombocytopenia, higher grade ≥3 adverse events) and was linked to elevated interleukin-6, suggesting its utility as a biomarker for patient stratification and potential benefit from combination therapy targeting IL-6.

IID432, a novel parasite-selective topoisomerase II inhibitor, achieved rapid single-dose sterile cure in a murine model of chronic Chagas disease. Mechanistically, it selectively stabilizes the parasite's TcTopoII-DNA cleavage complex by covalently engaging a parasite-specific cysteine (Cys477), ensuring selectivity over human TOP2A. This compound demonstrates superior potency, favorable pharmacokinetics, and an improved safety profile, offering a promising short-course therapy.

A systematic review and meta-analysis of six randomized controlled trials found that sacituzumab govitecan (SG) significantly improved progression-free survival, overall survival, and objective response rate compared to standard chemotherapy in patients with HER2-negative breast cancer. Although SG was associated with higher rates of neutropenia and diarrhea, its overall safety profile was manageable, reinforcing its role as an effective treatment for metastatic TNBC and HR+/HER2- breast cancer.

This research developed Horal HAMA-Nb@BM microgels for the precision oral treatment of bacterial enteritis, aiming to spatially confine antibacterial activity and minimize gut microbiota disruption. These microgels use Salmonella-specific nanobodies to capture and concentrate pathogens on their surface, subsequently releasing antibiotic-loaded vesicles that fuse with nearby bacteria for direct antibiotic delivery, which effectively reduced pathogen burden, preserved microbiota, and resolved inflammation in a murine infection model.

This rat study investigated the effects of permeation enhancers on the intestinal absorption of the poorly soluble and permeable PROTAC ARV-471, using *in vivo* absorption and permeability assays coupled with *in vitro* solubilization studies. It demonstrated that enhancers like salcaprozate sodium (SNAC) primarily improve absorption by increasing epithelial permeability, while others like lauroyl-l-carnitine (LLC) utilize a dual mechanism by also enhancing luminal solubilization, thereby offering strategies to improve oral bioavailability for PROTACs and similar BCS Class IV compounds.

Researchers developed a high-throughput screening assay to identify R5-1, a novel small-molecule inhibitor of the metallopeptidase nardilysin (NRDC), which acts via a non-competitive, allosteric mechanism. Pharmacological inhibition with R5-1 attenuated NRDC-dependent transcriptional repression of PGC-1α and significantly ameliorated inflammatory arthritis in a mouse model, highlighting NRDC's role in transcriptional regulation and disease.

This review synthesizes how microRNA (miRNA) dysregulation modulates core pathogenic cascades in polyglutamine (PolyQ) diseases, linking these mechanisms to disease phenotypes. It highlights promising miRNA-based therapeutic strategies, including AAV-delivered artificial miRNAs (with AAV5-miHTT in a human trial for Huntington's disease), and discusses the diagnostic potential of circulating miRNAs as stage-specific biomarkers, despite remaining translational challenges.

This paper proposes an operational framework to enhance the reliability of rs-fMRI-based neural representations in cognitive health RCTs, which are often limited by small sample sizes and high-dimensional data. The framework decouples representation development (using externally developed models) from trial-specific evaluation and distinguishes between pre-specified "target validation" and outcome-informed "target discovery." Demonstrated through two RCTs, this approach provides a robust method for accumulating evidence on intervention-responsive neural features.

This study screened 1,758 AI-designed protein binders against BCMA, CD19, and CD22 for their efficacy as CARs, using assays ranging from protein-binding to in vivo killing. Researchers identified critical challenges for these de novo binders, including tonic signaling, epitope occlusion, and off-target activity, and developed computational and experimental heuristics, like screening sequence variants, to overcome these liabilities while retaining on-target CAR activation.

This research developed ARO-RAGE, an inhaled siRNA therapy targeting RAGE mRNA to reduce pulmonary inflammation. Preclinical studies in various animal models demonstrated deep and durable RAGE silencing, limiting inflammation. A subsequent first-in-human Phase 1/2a trial confirmed ARO-RAGE's safety, tolerability, and effective pulmonary target engagement in healthy volunteers and asthma patients, supporting its continued clinical development.

Researchers synthesized novel hexahydro-1,8-acridinedione derivatives, featuring strategic N-aryl and C-9 biphenyl/bromophenyl modifications, and evaluated their potential as multi-targeted antitumor agents. Compound 4d emerged as the most potent, exhibiting high selectivity against H460 lung cancer cells (IC₅₀ = 17.91 µg/mL) and considerable anti-telomerase activity. In silico studies confirmed 4d's strong multi-target binding affinities to crucial cancer proteins like EGFR, TOP2B, p38 MAPK, and p53, establishing it as a promising multi-target lead scaffold.

This exposure-response analysis of enfortumab vedotin plus pembrolizumab in first-line urothelial cancer patients (EV-103, EV-302 studies) found that higher enfortumab vedotin exposures correlated with increased objective response rates and longer survival. Although higher exposures also led to more adverse events like hyperglycemia and skin reactions, these were effectively managed by dose modifications without compromising early treatment efficacy, thus supporting the existing 1.25 mg/kg starting dose in combination with pembrolizumab.

This study investigated the preclinical stability and integrity of a novel Auditory Nerve Implant (ANI) featuring penetrating microelectrodes, aiming to overcome limitations of traditional cochlear implants. Through accelerated thermal saline soak testing and extensive electrical stimulation (up to 6.3 billion pulses), the ANI electrodes demonstrated high integrity and stable impedances with minimal degradation, thereby supporting a 1.5-year in-dwelling period and readiness for clinical translation into human perceptual studies.

The phase 1 PAnTHA study evaluated the alpha-emitter [²²⁵Ac]Ac-PSMA-Trillium in 50 heavily pretreated metastatic castration-resistant prostate cancer patients, finding a manageable safety profile with no dose-limiting toxicities, though xerostomia was a common adverse event. This treatment demonstrated strong preliminary efficacy, achieving a 62% PSA50 response and a 50% overall response rate.

This computational study designed fusion-junction-specific antisense gapmers as potential therapeutic reagents for extraskeletal myxoid chondrosarcoma (EMC), an ultra-rare cancer driven by oncogenic _NR4A3_ fusions. Using an in-silico screening framework across 38 common fusion junctions, the researchers identified two lead 16-mer gapmers targeting the most reported _EWSR1_ and _TAF15_ to _NR4A3_ fusion breakpoints, applying a pre-registrable selectivity threshold to ensure specific cleavage of fusion transcripts over wild-type genes.

This research developed a DeepPurpose model to predict drug target inhibition constants (Ki) and empirically aligned these predictions with measured IC50 values, acknowledging they are not interchangeable. By refining the Ki training data from ChEMBL and applying a similarity-guided calibration method, the model significantly reduced prediction error, yielding surrogate IC50 estimates suitable for cross-target triage. This calibration is interpreted as a target- and chemistry-dependent empirical offset, not a mechanistic Ki-to-IC50 conversion.

This first-in-human study evaluated the biodistribution and radiation dosimetry of [⁶⁸Ga]Ga-ATH001, a PDGFRβ-targeting PET tracer for active fibrosis, in healthy and MASH participants. The tracer demonstrated an effective dose of 0.028 mSv/MBq with kidneys as the dose-limiting organ and was well-tolerated. These findings support its continued clinical development as a repeatable, non-invasive PET marker for active fibrosis.