Kymera Therapeutics

N6-Methyladenosine (m6A) represents the most prevalent internal RNA modification in eukaryotic mRNA, with YTHDC1 serving as a critical nuclear reader protein implicated in acute myeloid leukemia (AML). Although selective inhibitors of YTHDC1 have been reported, whether targeted degradation of YTHDC1 could achieve enhanced therapeutic efficacy remains unexplored. Here, we report the rational design and synthesis of the first PROTAC molecule targeting YTHDC1, termed XY-2, which was developed based on the cocrystal structure of YTHDC1 bound to its known inhibitor. XY-2 efficiently induced proteasome-dependent degradation of YTHDC1 at low nanomolar concentrations, with DC50 values of 11.42 nM in MOLM13 and 13.59 nM in Kasumi-1 cells. Functionally, XY-2 markedly inhibited proliferation, migration, and invasion, while robustly promoting apoptosis in multiple AML cell lines, with superior potency compared to its parent inhibitor. Transcriptomic and mechanistic analyses revealed that XY-2 downregulated genes associated with cell cycle, DNA replication, and mitotic progression, leading to G1 phase arrest. These findings establish XY-2 as the first highly efficient degrader of YTHDC1 and highlight targeted degradation of YTHDC1 as a promising therapeutic strategy for AML.

Hepatocellular carcinoma (HCC) is a type of cancer with a high incidence rate and a high mortality rate and is a major cause of cancer-related death. The resistance of liver cancer cells to lenvatinib has become a crucial limitation that restricts the clinical therapeutic efficacy of HCC treatment. In the present study, we successfully establish lenvatinib-resistant liver cancer cell lines and perform transcriptome sequencing analysis, through which we identify the key gene tripartite motif containing protein 31 (TRIM31). As an E3 ubiquitin ligase harboring a RING domain, TRIM31 is capable of regulating the stability and biological functions of its substrate proteins through ubiquitination. Nevertheless, the specific role and underlying molecular mechanisms of TRIM31 in liver cancer cell stemness and lenvatinib resistance remain largely unclear. In this study, clinical sample analysis confirms its high expression in HCC tissues, which correlates with poor patient prognosis. The results of functional experiments demonstrate that TRIM31 knockdown inhibits HCC stemness and lenvatinib resistance, whereas TRIM31 overexpression significantly enhances these properties. Mechanistically, TRIM31 interacts with glycine decarboxylase (GLDC) and mediates K48- and K63-linked polyubiquitination through its RING domain, leading to GLDC protein degradation. GLDC degradation enhances HCC stemness and chemoresistance by relieving its suppression of PI3K/AKT/mTOR signaling. This study is the first to highlight the critical role of TRIM31 in HCC stemness and drug resistance, offering a potential new strategy for targeted therapy in HCC.

Yes-associated protein (YAP), a key effector of the Hippo pathway, plays a well-established role in colorectal cancer (CRC). However, the functional relevance of site-specific post-translational modifications (PTMs) in YAP, particularly methylation, remains insufficiently explored. SET-domain-containing protein 8 (SETD8), the sole mono-methyltransferase for histone 4 lysine 20 (H4K20), is implicated in various cancers, yet its biological function and underlying mechanisms in CRC are elusive. While SETD8 is primarily known for its histone methylation activity, its capacity to modify non-histone proteins, such as YAP, remains largely unexplored. This study aimed to demonstrate that SETD8 exerted a tumor-suppressive effect on CRC by inhibiting YAP protein expression. Mechanistically, SETD8 physically interacts with YAP to catalyze mono-methylation at lysine 76 (K76me). This modification enhances the interaction between YAP and the E3 ubiquitin ligase RING finger protein 31 (RNF31), promoting YAP K48-linked polyubiquitination and subsequent proteasomal degradation. Clinically, patients with CRC and high SETD8 expression, including elevated YAP K76me levels, exhibited favorable pathological grading and improved prognosis. Collectively, our findings identify a novel SETD8-YAP K76me regulatory axis that restricts CRC progression, suggesting that targeting this axis may represent a promising therapeutic strategy.

A pivotal factor in the immune evasion of hepatocellular carcinoma (HCC) is the excessive exhaustion of CD8+ T cells; however, the molecular drivers of this phenomenon remain incompletely understood. In this study, we discovered that B7-H3 is markedly overexpressed in HCC and actively promotes CD8+ T cell exhaustion. Through high-resolution mass spectrometry and site-directed mutagenesis, we identified asparagine 215 (N215) as a critical N-linked glycosylation site of B7-H3. By employing dual orthogonal strategies-pharmacological inhibition via tunicamycin and targeted genetic ablation (N215Q mutation)-we provided strong evidence that, upon N215 glycosylation, B7-H3 maintains its cell-surface abundance through RAB11-mediated recycling of the endosomal pathway. Conversely, when glycosylation is impeded through either intervention, B7-H3 undergoes accelerated degradation via the endosome-lysosome route, thereby enhancing the cytotoxic activity of CD8+ T cells. Finally, murine experiments confirmed that both the specific genetic disruption of N215 and systemic blockade with tunicamycin enhance the antitumor effects of anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies. Collectively, our data reveal that the "B7-H3 Glycosylation-RAB11 Axis" preserves membrane expression of B7-H3, constituting an intrinsic mechanism of immune evasion in HCC, and uncover the intricate crosstalk between B7-H3 glycosylation and the immunosuppressive tumor microenvironment.

The TNF‑like cytokine TL1A is a key regulator of immune responses through engagement of its receptor, death receptor 3 (DR3), and has emerged as a therapeutic target in inflammatory diseases. Prevailing models propose that TL1A binding initiates recruitment of adaptor proteins to DR3, leading to downstream signaling. Here, we investigated proximal DR3 signaling events and found that the adaptor proteins TRADD and TRAF2 associate with DR3 independently of TL1A stimulation in both TF‑1 cells and primary human CD4+ T cells. In contrast, TL1A stimulation was strictly required for activation of NF‑κB signaling, including IκBα degradation and downstream ubiquitination events. These findings indicate that DR3 can exist in a preassembled adaptor complex prior to ligand engagement and suggest a revised model in which TL1A binding confers signaling competence rather than initiating adaptor recruitment. We propose a structurally informed, hypothesis‑generating model in which ligand engagement promotes higher‑order organization of prebound signaling components to enable downstream signal transduction. Together, our results refine current understanding of TL1A/DR3 signaling by decoupling adaptor assembly from ligand‑dependent signal activation.

Targeted protein degradation via molecular glues represents a powerful modality for modulating "undruggable" proteins. Herein, through proteomic profiling of a CRBN-binding library and rigorous structure-activity relationship (SAR) refinement, we report the discovery of dWBP4-1: a first-in-class, highly selective, CRBN-dependent molecular glue degrader of the spliceosome-associated scaffold protein WBP4. dWBP4-1 induces rapid, nanomolar degradation of WBP4 via a canonical G-loop-mediated mechanism, exhibiting exceptional proteome-wide selectivity with negligible transcriptomic or alternative splicing perturbation. Leveraging this highly specific target-glue interaction, we mapped the minimal WBP4 degron to a 41-amino-acid sequence to establish a compact, inducible chemical-genetic platform termed wTAG. When fused to diverse proteins of interest, wTAG enables robust, monotonic degradation devoid of the hook effect. While the wTAG system is highly versatile, we delineate its boundaries when applied to challenging targets like Cyclin D1, where factors such as steric hindrance, lysine availability, complex sequestration, and tag accessibility (N- vs. C-terminal fusion) must be carefully interrogated. Collectively, this study highlights the discovery of a highly selective WBP4 molecular glue and translates its underlying degron into a robust tool for precise protein control.

Periodontitis is a chronic immunoinflammatory disease characterized by site-specific destruction of the tooth-supporting tissues and marked heterogeneity in disease susceptibility, progression, and response to therapy. While dysbiotic subgingival biofilms initiate disease, microbial burden alone cannot explain the persistence of inflammation or the limited predictability of regenerative outcomes. Increasing evidence implicates innate immune dysregulation, particularly Toll-like receptor (TLR) signaling, as a central determinant of periodontal disease behavior. This narrative review synthesizes current evidence on TLR signaling in periodontal tissues, emphasizing the concept that chronic periodontitis is sustained by biased downstream signaling integration rather than uniform receptor overactivation. We discuss how persistent dominance of pro-inflammatory, MyD88-dependent pathways, coupled with insufficient engagement of regulatory and resolution-associated programs, promotes inflammatory persistence, osteoimmune imbalance, and functional impairment of periodontal stromal and stem/progenitor cells. Cell-type-specific responses to TLR activation, genetic modulation of signaling thresholds, and reciprocal interactions between innate immunity and dysbiosis are examined as key contributors to disease heterogeneity. We further explore the implications of biased TLR signaling for periodontal regeneration, proposing that regenerative failure reflects an unfavorable inflammatory signaling milieu rather than depletion of regenerative cell populations. Finally, emerging experimental strategies for interrogating and modulating TLR signaling networks-including localized immune modulation and targeted protein degradation approaches-are discussed as mechanistic research tools rather than immediate therapeutic solutions. By reframing periodontitis as a disorder of maladaptive innate immune signaling integration, this review provides a unifying conceptual framework linking dysbiosis, host-response heterogeneity, and impaired regeneration, and defines priorities for future mechanistic and translational research.