Kymera Therapeutics

Signal transducer and activator of transcription 6 (STAT6) is a key transcription factor in cytokine signaling, serving as the central effector of the IL-4 and IL-13 pathways. STAT6 orchestrates a range of physiological and pathological processes, including immune homeostasis and tumor development, making it an attractive therapeutic target for Th2-driven diseases and certain cancers. While the development of STAT6-directed agents remains at an early stage, the rapid clinical progression of the highly selective degrader KT-621 has revitalized interest in this target. In this review, we systematically summarize recent advances in STAT6 inhibitors and degraders, with a focus on structural features, design strategies, and biological evaluation. We also highlight current challenges and future opportunities, aiming to provide useful guidance for the discovery and optimization of next-generation STAT6-directed therapeutics.

The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.

Interferon regulator factor 3 (IRF3) inhibition is a shared strategy of many virally encoded proteins to effectively block the induction of interferon signaling. Although rotavirus nonstructural protein 1 (NSP1) is known to target IRF3 for proteasomal degradation, the exact molecular mechanism remains unclear. Here, we found that rotavirus NSP1 contains a BC box motif that mediates interaction with the Elongin BC complex. Either siRNA knockdown or CRISPR knockout of TCEB2, which encodes Elongin B, substantially prevented IRF3 degradation by NSP1. Recombinant rotaviruses that encode NSP1 with BC box mutations failed to degrade IRF3, induced elevated interferon responses, and were attenuated in interferon-competent cells in vitro and in vivo. NSP1 protein was significantly less stable in infected cells in the absence of Elongin B. Importantly, Elongin BC was required for the stability of additional BC box-containing viral antagonists, including pestiviral N proteases and human adenovirus E4orf6, indicating that Elongin BC functions not only as an adaptor for host protein degradation but also as a broadly exploited stabilizing factor for viral innate immune antagonists. This knowledge of virus co-opting of the host ubiquitin ligase machinery may instruct the development of broad-spectrum antiviral therapeutics.

Porcine Epidemic Diarrhea Virus (PEDV) causes highly contagious intestinal disease in swine and results in severe economic losses worldwide. PEDV Nsp3, a nonstructural protein produced in the early stage of viral replication, is responsible for cleaving polyproteins to generate nonstructural proteins and the replication-transcription complex, as well as inducing the formation of coronavirus replication organelles known as double-membrane vesicles (DMVs). Nsp3 is a key protein for viral replication; however, its specific mechanism of action remains unclear. To investigate the role of Nsp3 during viral infection, we performed LC-MS/MS analysis and identified 29 host proteins that potentially interact with Nsp3, among which RBM10 was selected for further study. This study confirms that RBM10 is a host factor that restricts PEDV replication, as validated by functional assays: RBM10 inhibits PEDV replication, while knockdown of RBM10 abolishes this inhibitory effect. This study proposes for the first time an RBM10-MARCHF9-Nsp3-p62 axis, which mediates the selective autophagic degradation of PEDV Nsp3. Mechanistically, RBM10 recruits the E3 ligase MARCHF9 to catalyze K33-linked ubiquitination of Nsp3. Subsequently, the ubiquitinated cargo is recognized by the selective autophagy receptor p62 and delivered to autophagosomes for degradation. Blocking autophagic flux, knocking down p62, or silencing key autophagy-related proteins restores Nsp3 protein levels. In summary, this study confirms RBM10 as a novel anti-PEDV host factor, providing new theoretical insights into host-directed regulatory mechanisms of PEDV replication and suggesting that RBM10 may serve as a potential target for the development of novel anti-PEDV strategies.

Immune checkpoint blockade (ICB), including PD-1/PD-L1 inhibitors, has transformed cancer therapy but benefits only a subset of patients. Understanding how PD-L1 is regulated and identifying strategies to overcome resistance remain critical. Here, we identify SIRT2 as a key positive regulator of PD-L1 across multiple human cancers. Unexpectedly, SIRT2 does not act at the transcriptional level but stabilizes PD-L1 protein by preventing ubiquitin-mediated degradation. Mechanistically, SIRT2 maintains the protein stability of USP22, a PD-L1 deubiquitinase. Loss of SIRT2 reduces USP22 levels, whereas ectopic USP22 fully rescues PD-L1 expression and reverses the enhanced antitumor immunity induced by SIRT2 inhibition. We further show that SIRT2 directly deacetylates USP22 at lysines 382 and 505 within its catalytic domain, promoting USP22 deubiquitinase activity and protecting both itself and its substrates from degradation. Our findings reveal a molecular mechanism by which an acetylation-deacetylation switch dynamically regulates deubiquitinase catalytic activity. Therapeutically, SIRT2 inhibition synergizes with PD-1/PD-L1 blockade and USP22 inhibition to enhance antitumor immunity. Consistently, protein but not mRNA levels of SIRT2, USP22, and PD- L1 positively correlate in human bladder cancer and melanoma. Together, these findings define a SIRT2-USP22-PD-L1 axis driving tumor immune evasion and highlight SIRT2 as a promising target to improve ICB efficacy.

Acute lung injury (ALI) is characterized by dysregulated pulmonary inflammation, in which alveolar macrophages (AMs) play a crucial role. The m⁶A reader protein YTHDF2, known to facilitate mRNA degradation, is implicated in inflammation; however, its specific function in ALI pathogenesis remains unclear. Using myeloid-specific Ythdf2 knockout mice subjected to cecal ligation and puncture (CLP)-induced ALI, we demonstrate that Ythdf2 deficiency significantly attenuates lung injury, as evidenced by reduced histopathological damage, pulmonary edema, and inflammatory cell infiltration, along with lower levels of pro-inflammatory cytokines (IL-6, TNF-α) in both bronchoalveolar lavage fluid and serum. Moreover, Ythdf2 deletion was accompanied by a substantial upregulation of Hmox1 protein expression in both lung tissues and AMs, an observation consistent with the known role of Ythdf2 in pulmonary hypertension. Furthermore, global m⁶A methylation levels and the expression of key methyltransferases (Mettl3, Mettl14) were elevated during ALI, coinciding with increased Ythdf2 expression. This upregulation of m⁶A regulators (YTHDF2, METTL3, METTL14) was also confirmed in pulmonary macrophages from human septic lungs. In conclusion, our findings support the concept that the myeloid-specific deletion of Ythdf2 ameliorates lung injury, an effect closely associated with the upregulation of Hmox1, highlighting Ythdf2 as a potential therapeutic target for ALI.

Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes (T2D), yet the underlying mechanisms remain incompletely defined. We hypothesized that elevated transforming growth factor beta 1 (TGFβ1) level is associated with impaired insulin sensitivity. Using primary hepatocytes, and mouse models with hepatic TGFβ1 overexpression or hepatic TGFβ1 signaling disruption, we examined the impact of TGFβ1 signaling on hepatic insulin signaling and glucose metabolism. We performed bulk RNA sequencing of liver samples identify potential mediator of obesity-induced insulin resistance. Immunoprecipitation, in vitro kinase assay, and mass-spec assay were used to explore the mechanisms underlying TGFβ1-induced insulin receptor substrate (IRS1) degradation. We further evaluated the therapeutic potential of targeting TGFβ1 signaling to improve glycemic control using the TGFβ1 signaling inhibitor LY2157299. Prolonged TGFβ1 exposure markedly reduced IRS1 protein abundance and impaired insulin-stimulated Akt activation in hepatocytes. Hepatic TGFβ1 overexpression exacerbated insulin resistance, whereas hepatic TGFβ1 signaling disruption improved insulin sensitivity by increasing IRS1 protein abundance. Mechanistically, TGFβ1 signaling increased Cullin 7 (CUL7) expression and promoted IRS1 phosphorylation at serine 685, leading to ubiquitin-dependent IRS1 degradation. Pharmacological inhibition of TGFβ1 signaling by LY2157299 improved insulin sensitivity in both lean and diabetic db/db mice. These findings identify TGFβ1 as a key driver of hepatic insulin resistance by promoting CUL7-dependent IRS1 degradation, establishing a mechanistic link between obesity-associated cytokine signaling and impaired insulin action and highlighting the TGFβ1-CUL7-IRS1 axis as a potential therapeutic target for T2D.