TL;DR
The design and synthesis of SHP2 PROTACs that recruit the DCAF16 E3 ligase for targeted SHP2 degradation are reported that support the potential of SHP2-targeted protein degradation as an alternative strategy to enzymatic inhibition and provide a promising starting point for the further development of SHP2 degraders.
Epithelial-mesenchymal transition (EMT) is essential for embryogenesis and tissue regeneration, yet its aberrant activation is closely associated with organ fibrosis and tumor metastasis. c-Jun N-terminal kinase 1 (JNK1) has been identified as a key mediator of transforming growth factor-β (TGF-β)-driven EMT, making it a promising therapeutic target. Herein, we describe the design, synthesis, and biological evaluation of a series of JNK1-targeting PROTACs that recruit either CRBN or VHL E3 ligases. Systematic structure-activity relationship optimization led to the discovery of compound YC2, which incorporates a newly developed VHL ligand modified with a 2,4-dimethyloxazole moiety, as a potent and selective degrader. YC2 induced efficient, concentration- and time-dependent degradation of JNK1 (DC₅₀ of 4.90 nM) via VHL-mediated ubiquitin-proteasome pathway engagement, while displaying strong selectivity over related kinases including JNK2, p38α, and ERK. Moreover, YC2 markedly attenuated TGF-β1-induced EMT, as evidenced by reduced fibronectin levels and restoration of E-cadherin expression, with efficacy comparable to nintedanib. Collectively, YC2 featuring a novel VHL ligand demonstrates excellent degradation potency and selectivity for JNK1, highlighting its potential as a valuable chemical probe for EMT-associated pathologies.
Abstract The ubiquitin-proteasome system (UPS) plays a central role in regulating protein homeostasis and degradation. Its dysregulation is closely associated with various diseases, including cancer. S-phase kinase-associated protein 2 (SKP2) is a key E3 ubiquitin ligase component of the UPS. It induces proteasome-mediated protein degradation or modulates substrate function by conjugating K48-linked or K63-linked ubiquitin chains to diverse target proteins. Recent studies have shown that the overexpression of SKP2 in several cancer types is correlated with poor clinical outcomes, underscoring its potential as a therapeutic target. Notably, emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment (TME) and immunotherapy response, positioning it as an increasingly attractive target for intervention. In this review, the oncogenic properties of SKP2 and its underlying mechanisms were elucidated in multiple cancer types. Moreover, we systematically summarized future directions for SKP2-targeted therapy.
Proteolysis-targeting chimeras (PROTACs) are currently constrained by a reliance on ubiquitously expressed E3 ligases, which compromises tumor selectivity and raises toxicity risks. Here, we identified KLHL12 as a potentially tumor-selective E3 ligase and reported the development of the first-in-class KLHL12-recruiting PROTACs. Guided by a structure-based macrocyclization strategy, we obtained a high‑affinity cyclic peptide, cp4, as a KLHL12‑binding ligand and constructed novel PROTACs against oncogenic BRD4 and EGFR. The optimal compound k12bp-1 achieved tumor-selective BRD4(L) degradation in A549 cells, significantly inhibiting cell proliferation and driving cell apoptosis while sparing normal cells. It demonstrated robust in vivo antitumor efficacy in A549 xenograft mouse models without observable systemic toxicity. Collectively, this work established KLHL12 as a promising tumor‑selective E3 ligase and provided a KLHL12-recruiting PROTAC platform for cancer therapy.
Ubiquitin-specific protease 2 (USP2), a pivotal member of the deubiquitinating enzyme family, has emerged as a critical but context-dependent regulator in cancer, exhibiting paradoxical tumor-suppressive and oncogenic functions. This duality is governed by its ability to stabilize specific substrate proteins, thereby modulating central signaling hubs including the p53, Wnt/β-catenin, PI3K/Akt, and cell cycle networks. Through these axes, USP2 profoundly influences hallmark cancer phenotypes such as sustained proliferation, metabolic reprogramming, metastatic progression, immune evasion, and therapy resistance. This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword. We detail how specific interactions between USP2 and its substrates dictate its pro-tumorigenic or anti-tumorigenic outcomes, depending on the tissue and microenvironment. Furthermore, we comprehensively evaluate the landscape of emerging USP2 inhibitors, discussing their therapeutic potential and the significant challenges posed by USP2's functional duality, substrate promiscuity, and isoform diversity. Targeting USP2 presents a promising yet intricate avenue for cancer therapy, necessitating future research focused on patient stratification, combination strategies, and the development of context-specific inhibitors.
To target the "undruggable" oncoprotein MYC, we developed MAX-7, an (i, i+7) all-hydrocarbon stapled peptide designed to induce MYC degradation via the chaperone-mediated autophagy (CMA) pathway. Compared to its linear precursor, MAX-7 displays increased α-helicity, enhanced proteolytic stability, and excellent cell permeability. Mechanistically, MAX-7 drives potent, lysosome-dependent depletion of endogenous MYC, bypassing the ubiquitin-proteasome system. Consequently, MAX-7 suppresses proliferation, migration, and invasion while triggering apoptosis in triple-negative breast cancer (TNBC) cells. In vivo, MAX-7 administration achieves significant tumor regression in a 4T1 xenograft model with a favorable biosafety profile. This study validates stapled peptide-based CMA degraders as a powerful strategy to target "undruggable" intracellular drivers, highlighting MAX-7 as a promising therapeutic lead.