Small-conductance calcium-activated potassium (SK) channels regulate excitability and calcium signaling in neurons, cardiomyocytes, and endothelial cells. Their dysfunction contributes to a broad spectrum of disorders, including neurodegenerative diseases, mood disorders, cardiac arrhythmias, and cancer. Despite extensive study, the specific physiological roles and pathological contributions of the SK1–3 subtypes remain incompletely understood. Latest advances in structural biology, computational modeling, and pharmacology have clarified the mechanisms underlying SK channel gating, modulation, and dysfunction. In this review, we integrate these novel insights to link structural and functional diversity with physiological and disease processes. We further discuss how subtype-selective modulators are shaping precision strategies for therapeutic development.

Membrane proteins are essential for cellular physiology and the target of half of all FDA-approved drugs. However, their hydrophobicity and low abundance make large-scale expression and purification difficult, posing a challenge for drug discovery. Despite these problems, mass spectrometry (MS) has enabled workflows for higher-throughput ligand screening, simplified identification of membrane protein targets and ligandable sites, and direct analysis of drug binding in native environments. In this review, we highlight emerging MS-based strategies, adapted workflows, and novel technological advances in different MS-based fields, including affinity selection, probe-based and probe-free chemoproteomics, and native MS that collectively expand our ability to interrogate membrane proteins for drug discovery, target deconvolution, and mechanistic characterization.

STRUCTURE: Sunvozertinib (Zegfrovy, CAS number: 2370013-12-8) is a small-molecule drug with the molecular formula of C29H35ClFN7O3 and molecular mass of 584.08 g/mol. Its IUPAC name is N-[5-[[4-[5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)anilino]pyrimidin-2-yl]amino]-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-4-methoxyphenyl]prop-2-enamide. This structure features two different substituted anilines attached to the pyrimidine ring.

Antibody–drug conjugates (ADCs) offer a promising approach for targeted cancer treatment. Progress, however, is constrained by the combinatorial complexity of design, toxicity and side effects, and variable clinical benefit across indications. Effective ADCs require rational matching of the antibody, linker, and payload to achieve stability in circulation and tumor-specific release, which makes development time- and cost-intensive. Artificial intelligence (AI) is shifting ADC development from empirical trial-and-error to data-driven, closed-loop engineering. By integrating sequence (for antibodies), structural, and molecular dynamics (MD) features of ADC components, AI models can accelerate target selection, conjugate optimization, and patient-response prediction. This review synthesizes advances in AI-driven ADC development across preclinical and clinical phases, highlights representative case studies and industry platforms, and outlines opportunities for AI-enabled next-generation ADCs.

Biased signaling by G protein–coupled receptors (GPCRs) occurs when ligands selectively activate G proteins or β-arrestins, offering therapeutic potential with fewer side effects. In class A GPCRs, which include the targets of approximately one-third of all marketed drugs, the structural basis of this selectivity remains unclear. Recent cryo–electron microscopy studies, supported by real-time functional assays such as bioluminescence resonance energy transfer and NanoLuc Binary Technology, reveal how distinct ligand binding modes reshape receptor conformations to favor specific transducer engagement. Integrating structural and functional insights enables mapping of isoform- and tissue-specific signaling. Here, we review key mechanisms of bias, including microswitch transitions, intracellular interface remodeling, and allosteric modulation, and provide a mechanistic basis for pathway-selective GPCR-targeting therapeutics with improved efficacy and reduced off-target effects.

Camelid-derived nanobodies offer a promising alternative to conventional antibodies for the treatment of brain disorders. Their current development in models of schizophrenia or Alzheimer's disease highlights their strong therapeutic potential. Optimizing their delivery and ensuring their safety are major challenges, but their modularity and low immunogenicity make them promising candidates for neurotherapy.

Bromodomain-containing protein 4 (BRD4) is a key transcriptional regulator in the bromodomain and extraterminal (BET) family. It promotes cancer and inflammation by binding to chromatin through its bromodomains. Although bromodomain inhibitors (e.g., BETi) show preclinical efficacy, their clinical application has been limited primarily by dose-limiting toxicities (DLTs), with resistance emerging as a secondary challenge. This motivates the development of strategies beyond conventional bromodomain inhibition. Here, we review emerging evidence that BRD4 sustains oncogenic programs through bromodomain-independent mechanisms, and discuss innovative approaches designed to overcome DLT. These include BRD4-targeted degraders, nonbromodomain ligands that disrupt scaffolding functions, post-translational modification (PTM) disruptors, and condensate modulators. We also discuss advances in chemically induced proximity (CIP) platforms that enable disease-state transcriptional reprogramming, and rational combination therapies (e.g., epigenetic-kinase inhibitors and BETi-immunotherapy integration) that minimize toxicity while addressing emerging resistance. Together, these approaches open new therapeutic frontiers for treating BRD4-driven diseases.

Many traditional psychostimulants used to treat neuropsychiatric disorders by targeting the dopamine transporter (DAT) exhibit a high potential of abuse. This necessitates the development of next-generation drugs with improved safety. Discovering atypical DAT inhibitors represent a promising strategy that may be facilitated by integration of structural pharmacology and artificial intelligence.

Small cell lung cancer (SCLC) progression relies on neuronal activity, yet the mechanisms remain unclear. Two recent studies by Savchuk et al. and Sakthivelu et al. reveal that SCLC co-opts vagal and sympathetic inputs and forms glutamatergic or GABAergic synapse-like connections with neurons, uncovering direct neuron–tumor crosstalk as a key driver of malignancy and a potential therapeutic vulnerability.

The WEE-family kinases, WEE1 and PKMYT1, play critical roles in regulating the G2/M cell cycle checkpoint to maintain genomic stability. Cancer cells with DNA damage response (DDR) deficiencies become heavily reliant on WEE1 and PKMYT1 to avert mitotic catastrophe. This dependence creates a synthetic lethality vulnerability that offers a promising therapeutic strategy. While early WEE1 inhibitors faced challenges due to toxicity, next-generation highly selective agents are now advancing through clinical trials with improved safety and efficacy. Similarly, PKMYT1 inhibitors have emerged as a complementary approach, with several candidates under clinical evaluation. This review examines the evolving mechanistic basis of synthetic lethality, with emphasis on how targeted inhibition of WEE1 or PKMYT1 exploits DDR defects to selectively induce genomic instability in cancer cells. Furthermore, we highlight recent advances in selective WEE kinase inhibitors, discuss key challenges, and explore innovative strategies to accelerate their development.

Dysregulated fibroblast growth factor receptor (FGFR) signaling – driven by amplifications, mutations, or fusions – represents a clinically validated oncogenic driver across diverse malignancies. Pan-FGFR-selective inhibitors (erdafitinib, pemigatinib, and futibatinib) have been developed in clinical practice. However, their therapeutic efficacy is substantially limited by inevitable on-target resistance mutations and toxicities via FGFR1/4 inhibition. Next-generation FGFR isoform-selective small-molecule inhibitors are emerging and represent active research frontiers. FGFR2-selective inhibitor lirafugratinib, FGFR3-selective inhibitors LOXO-435 and TYRA-300, FGFR2/3-selective inhibitor ABSK061, and FGFR4-selective inhibitors are in clinical development. Additionally, novel isoform-selective FGFR-targeting degraders, FGFR2b/FGFR3-selective antibodies, and de novo-designed ‘c’ isoform-selective proteins provide novel treatment strategies. This review provides an overview of the current FGFR-targeted therapeutics and limitations and evaluates next-generation inhibitor development to guide future research.

Sterile alpha and TIR motif-containing protein 1 (SARM1),is a central enzyme that drives programmed axon degeneration and has gathered significant interest as a therapeutic target. Despite preclinical development of inhibitory therapeutic approaches, clear evidence of the role of SARM1 in human neurodegeneration had been missing until recently. New discoveries demonstrate SARM1 involvement in widespread human neurodegenerative processes. Advances in understanding the mechanism of action of SARM1 have revealed key properties for developing the next generation of SARM1 inhibitors for neuroprotection. Unexpectedly, recent discoveries of pyridine-derived specific SARM1 activators have expanded the therapeutic possibilities for SARM1 beyond neuroprotection to include neuroablation. In this review, we discuss evidence linking SARM1 to human disease and the current challenges to developing safe and effective inhibitors. We also review the emerging field of SARM1 activators and their potential for the development of highly selective neuroablative therapeutics.

Neurodegeneration arises from malfunctional intercellular interactions within the central nervous system (CNS). In a recent study, Frosch et al. identified a microglia–neuron enzyme delivery system the dysfunction of which drives Sandhoff disease, but which can be corrected by hematopoietic replacement therapy, thereby revealing new therapeutic opportunities for hereditary and sporadic neurodegenerative disorders.

Cancer cells alter metabolic programs to support uncontrolled growth and proliferation. A new study from Scott and colleagues directly examined tumor metabolism in glioblastoma patients and discovered increased import of the amino acid serine. Excitingly, limiting serine uptake enhanced the effectiveness of chemoradiation in preclinical models of glioblastoma.

Drugs that reprogram the cellular ubiquitin-proteasome system for removal of disease-causing proteins hold great promise as a new type of pharmacology. Small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligases (StUbLs) are E3 ubiquitin ligases that mediate ubiquitylation of proteins primed by modification with SUMO. The antineoplastic drugs arsenic trioxide and fulvestrant stand out as examples for leveraging a SUMOylation-ubiquitylation cascade to inactivate the oncogenic fusion proteins PML-RARα and estrogen receptor α, respectively. However, approaches harnessing the StUbL system for targeting a broader spectrum of disease-relevant proteins are missing. Recent proof-of-concept studies indicate that proximity-inducing modalities can recruit aggregation-prone proteins to the StUbL machinery, potentially mitigating the formation of neurotoxic inclusions. We review new insights on StUbL-based therapeutics and reflect perspectives of reprogramming SUMO-StUbL signaling for use in oncology and neurology.

A central tenet of research articles is that they should accurately describe the experiments performed. Yet important aspects of experimental design and methods are sometimes omitted, precluding proper interpretation and follow-on studies. To remedy this, we urge researchers to adopt the CLEAR principle (Clarity, Evaluation, Assessment, Rigour) when reporting research.

Transcytosis across the blood–brain barrier (BBB) enables systemically administered large therapeutics to reach the brain parenchyma, but their fate in the parenchyma ultimately governs their therapeutic effect. Recent studies show that brain parenchymal cell uptake, internalization kinetics, reuptake at the BBB, and diffusion in the brain parenchyma shape the distribution and retention of therapeutics. Target engagement further influences their behavior beyond the BBB. These insights have prompted new strategies to enhance their distribution, retention, and target engagement. These include the selection of transport targets with favorable trafficking properties, the use of anchoring proteins, and modeling-based optimization. This opinion highlights emerging understanding of the fate of therapeutics in the brain parenchyma and outlines strategies to optimize this fate.

Metabolic derangements, particularly obesity and post-transplant diabetes mellitus, remain major challenges in solid organ transplantation, contributing to graft dysfunction and increased morbidity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising agents due to their glucose-lowering, weight-reducing, and cardiorenal protective effects. Accumulating evidence supports their efficacy in improving glycemic control, reducing body weight, and potentially enhancing graft and patient survival across diverse transplant populations. Notably, GLP-1RAs exhibit a favorable safety profile, with minimal risk of drug interactions or rejection. Early data also suggest immunomodulatory and anti-inflammatory benefits. Moreover, newer dual and triple incretin agonists offer enhanced metabolic efficacy, potentially extending these benefits further. While long-term outcomes remain under investigation, GLP-1RAs represent a compelling therapeutic option that may reshape metabolic management paradigms in both pre- and post-transplant care.

Adjuvants are substances used in vaccines to boost antigen-specific immune responses. Aluminum salts (alum) were the first adjuvant approved for human use. Unfortunately, they mainly induce antibody responses and are ineffective at eliciting strong T cell immunity, limiting their use in cancer vaccines. Recent advances reveal the mechanisms of various metal ions in modulating immune signaling. By integrating the synergistic immunomodulation of metal ion pairings with nanotechnology, bimetallic nanoadjuvants (BMNAs) are revolutionizing cancer vaccine. This approach overcomes the limitation of conventional single metal adjuvants by enabling multiplexed immune activation, leading to robust T cell responses for tumor control. This review highlights the immunological mechanisms of metal ions, the rationale behind their pairing in BMNAs, and current challenges for clinical translation.

Viruses are likely to cause future pandemics due to their inherent ability to evolve and spread rapidly, with limited treatment options. Engineered multivalent decoy receptors (EMDRs) offer a broad-spectrum alternative treatment option. We propose and evaluate EMDRs and their delivery methods to guide future efforts toward pandemic preparedness.

Psilocybin, a serotonergic psychedelic, is gaining attention for its rapid and sustained therapeutic effects in depression and other hard-to-treat neuropsychiatric conditions, potentially through its capacity to enhance neuronal plasticity. While its neuroplastic and therapeutic effects are commonly attributed to serotonin 2A (5-HT2A) receptor activation, emerging evidence reveals a more nuanced pharmacological profile involving multiple serotonin receptor subtypes and nonserotonergic targets such as TrkB. This review integrates current findings on the molecular interactome of psilocin (psilocybin active metabolite), emphasizing receptor selectivity, biased agonism, and intracellular receptor localization. Together, these insights offer a refined framework for understanding psilocybin’s enduring effects and guiding the development of next-generation neuroplastogens with improved specificity and safety.