Aug 2026· Journal of Medicinal Chemistry· Vol 69 15, pp.
18076-18098
· 0 citations· 50 references
Medicine
TL;DR
A dual-targeting strategy aimed at simultaneously inhibiting the oncogenic protein-protein interaction between UBE2M and DCN1, which is critical for neddylation-dependent activation of cullin-RING ligases (CRLs) and histone deacetylase (HDAC) activity is developed.
Abstract
Resistance to monotherapy remains a major challenge in the treatment of nonsmall cell lung cancer (NSCLC), highlighting the need for innovative therapeutic strategies. To address this issue, we developed a dual-targeting strategy aimed at simultaneously inhibiting the oncogenic protein-protein interaction (PPI) between UBE2M and DCN1─which is critical for neddylation-dependent activation of cullin-RING ligases (CRLs)─and histone deacetylase (HDAC) activity. Inspired by the synergistic antitumor effects observed with combined inhibition of UBE2M-DCN1 and HDAC, we designed hybrid molecules integrating pharmacophores targeting both pathways. Our preferred compound JN210 effectively disrupts the UBE2M-DCN1 interaction and inhibits HDAC, demonstrating significantly enhanced cytotoxicity compared to the parent compounds in vitro and potent tumor growth suppression in vivo. Mechanistic studies revealed dual blockade of CRL neddylation and induction of histone hyperacetylation, resulting in impaired DNA damage repair and synergistic apoptosis. As a novel DCN1/HDAC dual inhibitor, JN210 represents a promising therapeutic candidate for NSCLC.
Epigenetic drugs offered a novel disease therapeutic strategy by reversibly modulating gene expression. For instance, inhibitors targeting histone lysine demethylases (KDMs) and histone deacetylases (HDACs) demonstrated significant potential in combating complex diseases such as cancer and neurological diseases. However, single-target inhibitors often exhibit limited efficacy or resistance due to the complexity of disease mechanisms and the activation of compensatory pathways. To address these limitations, a series of novel quinazoline derivatives were designed and synthesized as potent dual inhibitors targeting histone lysine demethylase JMJD3 and histone deacetylases. Through systematic structural optimization, lead compound 6a was identified with nanomolar potency: JMJD3 (IC50 = 545 nM), HDAC1/2/3/6/10 (IC50 = 1.1/3.5/4.4/16/8.3 nM), along with significant selectivity over related isoforms including JMJD1B, JMJD2A and HDAC8. The cellular enzymatic inhibition activity was validated in triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and HCC1806, where 6a dose-dependently elevated the levels of H3K27 methylation (me1/me2/me3) and H3 acetylation. The therapeutic potential of these JMJD3/HDAC inhibitors was further evaluated in TNBC cell models, where they exhibited potent antiproliferative activity and induced cell cycle arrest. Compared with previously reported JMJD3/HDAC dual inhibitors, 6a demonstrates superior nanomolar potency against both targets. As a highly potent lead, 6a provides a novel scaffold for dual-target epigenetic drug discovery, a valuable chemical probe for investigating epigenetic crosstalk, and a promising candidate for cancer therapy.
This study aimed to develop dual-target inhibitors against Aurora A and HDACs, and identified Z20 as the optimal candidate via in vitro screening. Z20 showed non-selective HDAC inhibitory activity and potent anti-tumor effects, significantly inhibiting the growth of 5 tumor cell lines (including Jurkat, HCT116) with efficacy superior to positive control CAM2602. It dose-dependently induced apoptosis and G2/M phase arrest in Jurkat and HCT116 cells, and specifically regulated the Aurora A/HDAC pathway by downregulating p-Aurora A and upregulating HDAC substrates Ac-H3/Ac-α-tubulin. However, Z20 exhibited poor in vivo efficacy (TGI: 47.2% vs. 62.7% for CAM2602) in NOG mice bearing Jurkat xenografts. Metabolic and pharmacokinetic evaluations revealed that Z20 had unfavorable properties: extremely short half-life (17.6 min), high intrinsic clearance (0.08 mL min-1 mg-1), and low oral bioavailability (0.3%), which accounted for its suboptimal in vivo performance. In conclusion, Z20 is a potent Aurora A/HDAC dual-target inhibitor in vitro, while its pharmacokinetic defects limit clinical potential. This study highlights the necessity of optimizing pharmacokinetic profiles for translating in vitro potency to in vivo efficacy.
Lirong Zhang, Xuewen Zhang, Jie Zhong et al.· RSC Medicinal Chemistry· 0 citations
The epigenetic regulator protein arginine methyltransferase 5 (PRMT5) is aberrantly overexpressed in triple-negative breast cancer (TNBC) and represents a promising therapeutic target. Currently reported PRMT5-targeting PROTAC degraders (MS4322 and MS115) are both derived from a tetrahydroisoquinoline scaffold. These compounds require treatment for more than five days to exert effective antiproliferative activities, and no in vivo antitumor efficacy has been reported. To address these limitations, we adopted the carbazole-based PRMT5 inhibitor PJ-68, which features a lower molecular weight and a more accessible linker attachment site. Herein, we reported a series of novel PRMT5 degraders with carbazole scaffold. The representative compound YZ-17 degraded PRMT5 (DC50 = 2.2 μM in HCC1806 and 3.3 μM in HCC1937 cells) and its adaptor protein MEP50 (DC50 = 2.0 μM and 2.9 μM, respectively) within 24 h. YZ-17 also suppressed PRMT5-mediated symmetric dimethylarginine (sDMA) modification and colony formation, induced G1 phase cell cycle arrest, and displayed favorable antiproliferative activities across several TNBC cell lines (IC50 = 2.6 - 3.7 μM). Importantly, YZ-17 showed in vivo efficacy in an HCC1806 xenograft model, achieving a tumor growth inhibition (TGI) of 44.12% at 30 mg/kg (i.p., every other day) without obvious toxicity. Collectively, YZ-17 represents a structurally novel PRMT5 degrader with rapid onset of action, effective in vitro and in vivo anti-TNBC activity, offering a distinct chemical tool for further functional studies of PRMT5.
Yuzhan Li, Yaxun Guo, Dazhao Mi et al.· European journal of medicina...· 0 citations
Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase IIβ-binding protein 1 (TopBP1), a multifunctional scaffold protein with nine BRCT domains, integrates replication stress signaling with oncogenic networks and is frequently overexpressed in aggressive cancers. Its BRCT7/8 domains mediate critical interactions with E2F1, mutant p53, MIZ1, PLK1, and CIP2A, making TopBP1-BRCT7/8 an attractive therapeutic target. Using docking-guided screening and structure-activity relationship–driven optimization, we developed CS18 as a potent and selective BRCT7/8 inhibitor that disrupts oncogenic TopBP1 complexes without interfering with DNA replication. CS18 suppresses MYC transcriptional programs, restores E2F1-mediated apoptosis, and induces mitotic catastrophe. It exhibits broad-spectrum anticancer activity and synergizes with poly(ADP-ribose) polymerase (PARP) inhibitors in multiple cancer types and enhances osimertinib sensitivity in EGFR-mutated non–small cell lung cancer (NSCLC) cells. CS18 demonstrates efficacy in patient-derived breast cancer xenografts and overcomes osimertinib resistance in refractory NSCLC in vivo. These findings establish CS18 as a chemically distinct TopBP1 inhibitor with translational potential to overcome therapeutic resistance and advance precision oncology.
Fang-Tsyr Lin, Shwu-Jiuan Lin, Kang Liu et al.· Science Advances· 0 citations
Synergistic strategies are urgently needed to enhance the efficacy of immunotherapy in lung cancer. Recent evidence highlights Enhancer of zeste homolog 2 (EZH2) as a pivotal epigenetic regulator that fosters an immunosuppressive tumor microenvironment, thereby driving immunotherapy resistance. We hypothesized that EZH2 pharmacological inhibition could increase immunotherapy susceptibility. This study aimed to investigate the potential of a novel EZH2 inhibitor, XNW5004, to sensitize lung adenocarcinoma (LUAD) to programmed cell death protein 1 (PD-1) blockade. In vitro, colony formation and apoptosis assays assessed direct cytotoxicity of XNW5004 on tumor cells at 0–12 µM. A co-culture system of tumor cells and peripheral blood mononuclear cells evaluated immune-mediated killing. In vivo, immunodeficient nude mice and immunocompetent C57BL/6 mice were randomly assigned to the control, XNW5004, anti-PD1, and combination groups to assess the tumor suppressive effect. Underlying mechanisms were explored through RNA sequencing alongside comprehensive cellular and molecular assays. In vitro, pre-treating tumor cells with 1.5 µM XNW5004 enhanced their sensitivity to immune cell attack, resulting in fewer residual cells and increased apoptosis, an effect further potentiated by PD-1 blockade. In vivo, XNW5004 suppressed tumor growth in immunocompetent C57BL/6 mice but showed minimal effect in immunodeficient nude mice. Mechanistically, XNW5004 stimulated chemokine-mediated recruitment of dendritic cells and T cells into tumor sites. Additionally, it upregulated the antigen presentation molecule major histocompatibility complex class I (MHC-I), while simultaneously augmenting the expression of co-signaling molecules programmed death ligand 1(PD-L1) and intercellular adhesion molecule-1 (ICAM-1). These alterations contributed to the augmented cytotoxic activity of both CD8+ T cells and natural killer cells, as evidenced by increased interferon-γ and granzyme B. The STING-TBK1-NF-κB axis functions as a pivotal regulatory signaling pathway driving these phenotype alterations. The EZH2 inhibitor XNW5004 enhances anti-tumor immunity and synergistically interacts with PD-1 blockade immunotherapy in LUAD, establishing this combinatorial approach as a promising therapeutic strategy.
Zhihuan Lin, Wenjuan Ma, Haishuang Sun et al.· Journal of Translational Med...· 0 citations
The development of dual inhibitors of histone deacetylases (HDACs) and enhancer of zeste homologue 2 (EZH2) is an efficient strategy that not only synergistically suppresses critical pathways in tumorigenesis but also circumvents the potential risks of drug cocktails. In this study, a series of pyridone derivatives were rationally designed via pharmacophore merging, and N1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N8-hydroxyoctanediamide (15c) was identified as the most potent compound against hematological tumor cells MV4-11 and SU-DHL-10, with IC50 values in the submicromolar range. 15c also effectively inhibited HDAC1 and EZH2 with IC50 values of 9.2 nM and 311.1 nM, respectively. Molecular simulations revealed key interactions between 15c and both targets. These findings indicated that compound 15c warrants further investigation as a novel dual HDAC/EZH2 agent.
