Kymera Therapeutics

Osteoarthritis (OA) is increasingly recognized as a mechanically driven whole-joint disease in which abnormal mechanotransduction initiates a cascade of mitochondrial dysfunction, chronic inflammation, and progressive cartilage degeneration. Among the mechanosensitive molecules identified to date, Piezo1 has emerged as a key mechanosensitive regulator linking pathological mechanical loading to intracellular calcium signaling and downstream cellular responses. Growing evidence indicates that persistent Piezo1 activation promotes mitochondrial calcium overload, excessive reactive oxygen species production, ATP depletion, mitochondrial membrane depolarization, and impaired mitophagy, ultimately amplifying chondrocyte dysfunction and extracellular matrix degradation. In parallel, mitochondrial damage triggers immunometabolic reprogramming through activation of the cGAS-STING pathway and the NLRP3 inflammasome. It also promotes pro-inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α, and interleukin-6. Together, these responses may contribute to a self-perpetuating cycle of inflammation and tissue destruction. This review provides a comprehensive synthesis of recent advances regarding the role of Piezo1 in OA, focusing on the mechanistic links between mechanotransduction, mitochondrial dysfunction, mitophagy, and immunometabolic dysregulation. We further discuss the contribution of mitochondrial quality-control pathways, including PINK1/Parkin-, BNIP3-, and FUNDC1-mediated mitophagy, as well as alterations in mitochondrial dynamics involving DRP1, MFN1, MFN2, and OPA1. Emerging experimental models are discussed as valuable tools for accelerating therapeutic discovery. Finally, we critically evaluate current therapeutic strategies targeting the Piezo1-mitochondria axis, including mechanosensitive channel modulation, mitochondrial protection, mitophagy enhancement, gene therapy, biomaterial-assisted delivery, and nanomedicine. Collectively, current evidence supports the Piezo1-mitochondria-immune axis as an important mechanistic framework contributing to OA pathogenesis and as a potential therapeutic target. Integrating mechanobiology, mitochondrial medicine, and precision-engineered experimental models may facilitate the development of next-generation disease-modifying therapies capable of slowing or preventing osteoarthritis progression.

The mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a central regulator of inflammatory signaling downstream of immunoreceptor tyrosine-based activation motif-containing receptors and G protein-coupled receptors (GPCRs). MALT1 has been investigated as a drug target in inflammation and cancer by inhibitors and targeted degradation. Accurate quantification of MALT1 protein is a critical unmet need for drug discovery. However, traditional ligand binding assays (LBAs), such as Enzyme-Linked Immunosorbent Assay (ELISA) or Meso Scale Discovery Assay (MSD), have been limited by the lack of suitable reagents. To address this limitation, we developed LC-MS/MS targeted MALT1 degradation monitoring assays which have enabled effective monitoring of target degradation in vivo and in vitro. A customized, reagent-independent one dimensional (1D)-LC-MS/MS assay was initially used to facilitate early-phase drug discovery screening. Furthermore, the continued progress of the discovery chemistry resulted in molecules with a higher percentage of MALT1 degradation, resulting in lower remaining MALT1 concentrations within sample matrices and the need for a highly sensitive quantitation. Consequently, a 2D-LC-MS/MS assay with a novel instrument configuration was developed. This assay has proven crucial for early drug optimization and dose selection in both in vitro and in vivo studies. The examples of assay application include the measurement of the DC50 of a lead compound across multiple species, with DC50 value of 5.2 nM in monkeys, 57.0 nM in rats, and 86.9 nM in dog splenocytes. This assay was also used to help select one of the best lead compounds with degradation showing 77.9% with in vivo treatment.

Real-world data on the healthcare resource utilisation (HCRU) and cost burden of eosinophilic granulomatosis with polyangiitis (EGPA) are limited. We assessed all-cause HCRU and costs in patients with EGPA versus a matched general population cohort without EGPA and a severe uncontrolled asthma (SUA) cohort. Primary care data in England from the Clinical Practice Research Datalink Aurum database, with linkage to Hospital Episode Statistics inpatient, outpatient and emergency department records, were analysed. Patients with a new EGPA diagnosis in 2006-2020 and ≥ 1 year of data before diagnosis (index date [ID]) were included and matched using a matching ratio of up to 1:4 with a general population cohort without EGPA and patients with SUA. Follow-up was from ID until deregistration, last data collection, death or study end. HCRU and associated costs were assessed across the 12 months prior to ID, and annually from ID to end of the study period, and by disease states and Five-Factor Score [FFS]. A total of 486 patients with EGPA were identified, with a corresponding matched general population cohort of 1938 and SUA cohort of 1005 patients. Annual all-cause HCRU rates during follow-up were higher in the EGPA cohort versus the general population and SUA cohorts for all types of care, particularly in the first year after ID. Patients with an FFS of 0 generally had lower HCRU than those with an FFS ≥1. Annualised total HCRU-associated costs (95% confidence interval [CI]) were higher in the EGPA cohort (£13,978 [12,068, 15,888]) versus the general population (£2303 [2145, 2461]) and matched SUA cohorts (£3571 [3326, 3816]), with cost ratios (95% CI) of 8.3 (7.1, 9.6) and 4.1 (3.6, 4.6) respectively, both p < 0.0001. The greatest cost driver was hospital admissions with cost ratios (95% CI) of 12.3 (9.8, 15.5) and 5.8 (4.7, 7.2) compared with the general population and SUA cohorts, respectively. Median all-cause annualised total costs per patient were 46% and 56% higher among patients with relapse or stable disease, respectively, than among those in remission at ID. Patients with EGPA incurred significantly higher annualised HCRU rates and associated costs than both the general population and SUA cohorts, underscoring a substantial clinical and economic burden and highlighting a persistent unmet clinical need in practice.

Neuroinflammation represents a common pathological mechanism underlying a wide range of central nervous system (CNS) disorders, encompassing neurodegenerative disorders (NDDs), ischemic stroke (IS), traumatic brain injury (TBI), and demyelinating diseases such as multiple sclerosis (MS). This process is initiated by the orchestrated responses of microglia, astrocytes, oligodendrocyte-lineage cells, neurons, brain endothelial cells, and infiltrating peripheral immune cells. Neuroinflammation can facilitate tissue repair or, conversely, perpetuate chronic inflammation and neural damage. Post-translational modifications (PTMs) serve as critical mediators linking extracellular danger signals and intracellular metabolic conditions to alterations in protein activity, stability, localization, interactions, and degradation. Notably, the biological impact of a PTM cannot be solely deduced from its classification; rather, it is contingent upon factors such as the specific enzyme responsible for its addition or removal, the identity of the substrate, the modified residue or ubiquitin-chain architecture, the subcellular localization, the cellular context, and the stage of the disease. In this review, we synthesize evidence on various PTMs such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, glycosylation, S-nitrosylation (SNO), and metabolite-coupled modifications, including lactylation and succinylation. We analyze their convergent and divergent roles across different neuroimmune cell types, disease-related stimuli, and temporal contexts, and investigate the mechanisms by which intercellular communication propagates PTM-dependent inflammatory signals. Special emphasis is placed on the ordered and competitive crosstalk among PTMs that modulate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor protein 3 (NLRP3) inflammasome, and JAK-STAT signaling pathways, as well as the integrity of the blood-brain barrier (BBB), oligodendrocyte differentiation, and remyelination processes. Additionally, we assess PTM-regulating enzymes as potential therapeutic targets, while highlighting current limitations such as uneven cell-specific evidence, extrapolation from non-neural systems, low modification stoichiometry, rapid turnover, tissue-processing artifacts, and the insufficiency of transcriptomic data alone to demonstrate site-specific protein modifications. The integration of single-cell and spatial multi-omics with PTM-enrichment proteomics, quantitative site-occupancy assessments, and orthogonal mechanistic validation is anticipated to facilitate the generation of PTM maps that are resolved at the cellular, site-specific, and developmental stage levels. This evidence-based framework has the potential to enhance biomarker-guided disease stratification and inform the development of more selective, brain-targeted therapeutic interventions for neuroinflammatory disorders. CLINICAL TRIAL NUMBER: Not applicable.

This work reports on the development of selective histone deacetylase 6 (HDAC6) degraders based on a peptoid scaffold. Structure-based design identified the isocyanide-derived cap region as suitable exit vector for linker attachment, enabling rapid generation of CRBN-recruiting PROTACs via the Ugi four-component reaction. A focused library of 12 degraders revealed a strong dependence of activity on linker composition, with octyl-linked compounds (9e-h) showing the strongest HDAC6 degradation with half-maximal degradation values of 17-36 nM in kinetic HDAC6 degradation assays. The lead compounds selectively degraded HDAC6 in MM.1S and MV4-11 cells without affecting class I HDACs and demonstrated clean proteomic profiles. Functionally, compounds 9e and 9f displayed submicromolar antiproliferative activity against FLT3-ITD-mutated acute myeloid leukemia cells and suppressed proinflammatory signaling in immune cells. Both effects were associated in part with residual class I HDAC inhibition. Overall, this study establishes an efficient multicomponent strategy for PROTAC synthesis and highlights key structure-degradation relationships.

The combination of radiation therapy and immunotherapy has become a cornerstone of modern clinical cancer treatment. However, the inherent radiation resistance of tumors and complex immune evasion mechanisms remain major bottlenecks limiting their long-term effects and sustained efficacy. E3 ubiquitin ligases critically influence tumor sensitivity to radioimmunotherapy by controlling protein stability across DNA repair, immune signaling, and stress-response pathways. This review systematically dissects the multidimensional molecular network through which E3 ubiquitin ligases regulate radiosensitivity and immunoresponsiveness. At the intracellular level, we provide an in-depth analysis of how E3 ubiquitin ligases determine the fate of radiation-induced damage repair by precisely regulating the kinetics of the DNA damage response (DDR), cell cycle checkpoints, and apoptosis thresholds. At the extracellular level, this study focuses on the key roles of E3 ubiquitin ligases in reshaping the immune microenvironment, including the maintenance of spatiotemporal stability of immune checkpoints, the fidelity of antigen processing and presentation, and the epigenetic regulation of microenvironmental dynamic plasticity. Recent studies indicate that E3 ubiquitin ligases link radiation-induced DDR signaling to innate and adaptive immune activation, particularly through the induction of immunogenic cell death (ICD) and the calibration of innate immune sensing pathways like cGAS-STING. Finally, we provide a comprehensive synthesis of cutting-edge translational strategies targeting E3 ubiquitin ligases-ranging from canonical inhibitors to transformative proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs)-offering novel paradigms for overcoming therapeutic resistance and refining personalized radioimmunotherapy.

Gastric cancer (GC) derives limited benefit from immunotherapy, with clinical responses observed in only a minority of patients. Increasing evidence suggests that heterogeneity within the tumor immune microenvironment (TME) is a critical determinant of immunotherapeutic efficacy, highlighting the need for precise immune stratification and the identification of molecular biomarkers that shape the TME. We integrated single-cell transcriptomic data from our cohort and public datasets to characterize immune microenvironment heterogeneity in GC. Functional experiments were performed using in vitro assays and in vivo mouse models to investigate the molecular mechanisms regulating immune exhaustion. Clinical relevance was evaluated using tumor specimens from patients with GC receiving anti-programmed cell death protein 1 (PD-1) therapy. Survival analyses and biomarker evaluation were conducted to assess the prognostic and predictive value of candidate markers. We identified two distinct GC immune microenvironment subtypes: the immunosuppressive (GC1) and the immune-activated (GC2). PRKX was identified as a key regulator associated with immune heterogeneity and exhaustion. Clinically, a high density of PanCK+ PRKX+ PD-L1+ tumor cells was significantly associated with poor prognosis and served as a robust biomarker predicting 5-year survival in patients treated with anti-PD-1 therapy. Mechanistically, PRKX phosphorylates programmed death-ligand 1 (PD-L1) at T285, promoting YWHAE recruitment and preventing UBE2M-mediated ubiquitination and degradation, thereby stabilizing PD-L1 protein. Through this phosphorylation-dependent regulation of PD-L1 stability, PRKX suppresses CD8+ T-cell cytotoxicity, promotes immune exhaustion, and limits the efficacy of anti-PD-1 therapy in vivo. Therapeutically, lipid nanoparticle-mediated delivery of PRKX-targeting siRNA effectively suppressed PRKX expression and synergized with anti-PD-1 therapy to enhance antitumor efficacy. PRKX drives immune exhaustion in the GC1 subtype by stabilizing PD-L1 through phosphorylation-dependent inhibition of ubiquitination, thereby promoting immune evasion. Targeting PRKX represents a potential strategy to overcome resistance to anti-PD-1 therapy, and PRKX expression may serve as a prognostic biomarker to guide immunotherapy in GC.