Jul 2026· European journal of medicinal chemistry· Vol 317, pp.
119124
· 0 citations· 39 references
Medicine
TL;DR
G2 is established as a promising therapeutic candidate for surmounting sorafenib resistance, characterized by selective antitumor activity against malignant hepatocellular carcinoma.
Abstract
Drug resistance is a major barrier to effective hepatocellular carcinoma therapy, and autophagy targeting holds great potential for overcoming this issue. Using binding energy data from molecular docking with TBC1 domain family member 2 (TBC1D2) as the target, we rationally designed compound G2 featuring a piperazine moiety. Target binding was validated via a competitive immunofluorescence assay. The binding affinity of G2 was determined by surface plasmon resonance, yielding a dissociation constant (KD) of 0.4 μM. Functional evaluation of G2 determined its aqueous solubility to be 0.3 mg/mL, with a half-maximal inhibitory concentration value of 80 ± 20 nM and a selectivity index of 23.1 in HCCLM3 cells. Subsequent mechanistic investigations revealed that this selectivity arose from the heightened responsiveness of TBC1D2 expression to G2 in HCCLM3 cells, thereby inducing selective autophagic cell death. In HCCLM3 xenograft mouse models, G2 showed excellent hepatic retention. G2 monotherapy (58.2% tumor growth inhibition) and its combination with sorafenib (70.9%) exerted superior antitumor activity versus sorafenib monotherapy (52.8%), with favorable safety. Collectively, our findings establish G2 as a promising therapeutic candidate for surmounting sorafenib resistance, characterized by selective antitumor activity against malignant hepatocellular carcinoma.
Summary Hepatocellular carcinoma (HCC) still has limitations such as tumor resistance, recurrence, and poor prognosis. Therefore, the development of anticancer drugs with mechanisms of action is of great significance for the treatment of HCC. In this study, we identified KZL-064, a 2-trifluoromethyl-4-aminoquinazoline derivative, which markedly inhibits HCC cell proliferation, migration, and invasion, induces apoptosis and G2/M arrest, and, in MHCC97-H xenograft mice, oral administration achieves tumor suppression comparable to that of sorafenib without significant toxicity. Through virtual screening, molecular docking, cellular thermal shift assay (CETSA), and biologic layer interferometer (BLI), we identified histone deacetylase 1 (HDAC1) as a direct binding target. Knockdown of HDAC1 partially attenuates pro-apoptotic and cell-cycle effects, yet does not impair anti-migratory/invasive activities nor completely abolish overall efficacy. Collectively, KZL-064 emerges as a promising lead, and its anti-proliferative action likely involves multi-target mechanisms engaging HDAC1 and p53-associated apoptotic signaling, offering a conceptual framework for HCC therapy.
Shimei Wang, Xudong Cui, Gang Yu et al.· iScience· 0 citations
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.
Tao Zheng, Yigui Li, Yunyuan Huang et al.· Journal of Medicinal Chemist...· 0 citations
Hepatocellular carcinoma (HCC) remains a significant clinical challenge, and targeting the dual phosphorylation of signal transducer and activator of transcription 3 (STAT3) has emerged as a promising strategy for HCC treatment. In this study, 25 novel β-carboline-benzo[b]thiophene 1,1-dioxide hybrids were designed and synthesized via structural modification of the β-carboline scaffold. Among them, compound 18 exhibited the most potent antiproliferative activity against Huh-7 cells in vitro, with an IC50 value of 1.30 ± 0.05 μM, and significantly suppressed colony formation and cell migration. Mechanistic investigations demonstrated that compound 18 directly bound to STAT3 protein with a KD value of 5.63 μM, as determined by surface plasmon resonance (SPR), and markedly inhibited its phosphorylation at both Tyr705 and Ser727 residues, consequently blocking its nuclear translocation. In addition, compound 18 impaired mitochondrial function by reducing ATP production and elevating reactive oxygen species (ROS) levels. In a Huh-7 xenograft mouse model, compound 18 administered at 7.5 mg/kg achieved a tumor inhibition rate of 55.08%. Collectively, these results indicate compound 18 as a promising STAT3 dual phosphorylation inhibitor for HCC treatment.
Ziqing Jian, Lanyi Wei, Meilin Ren et al.· European journal of medicina...· 0 citations
The data support a model in which HDAC1 inhibition is associated with mitochondrial dysfunction and mitophagy, contributing to tumor suppression, and highlights the potential of iodo-phenanthroimidazole derivatives as a novel therapeutic strategy for glioblastoma.
The urgent need for novel glioblastoma (GBM) therapies has motivated the exploration of EGFR G-quadruplex (G4) targeting, which suppresses oncogene transcription independently of kinase activity. However, existing EGFR G4 ligands lack subtype selectivity. Through computer-aided design and systematic bioisosteric modifications of the 1H-imidazo[4,5-f][1,10]phenanthroline scaffold, we synthesized a series of derivatives. We evaluated their G4 interactions by molecular docking, UV-Vis, FRET, ITC, and CD. Compound 3, bearing a 6-bromopiperonyl group, exhibited nanomolar affinity for EGFR G4 (Kd = 102 nM) with ~146-fold selectivity over K-Ras G4, stabilizing it via end-stacking. It potently inhibited U87-MG glioblastoma cell proliferation (IC50 = 0.49 μM), with a wide safety margin relative to normal HMC3 microglia (safety index = 14.18). Mechanistically, compound 3 triggered DNA damage, mitochondrial oxidative stress, and sequential multi-organelle damage to mitochondria, lysosomes, and the endoplasmic reticulum, while impairing cell migration and invasion. These findings establish compound 3 as a uniquely selective EGFR G4 stabilizer, offering a promising multi-organelle-damage strategy for glioblastoma therapy.
Mengjiao She, Ao Yu, Xiao-Zhan Qiu et al.· Antioxidants· 0 citations
PE-1 demonstrates dual-target inhibitory activity against the PD-1/PD-L1 immune checkpoint and EZH2, underscoring its potential as a lead compound for the development of next-generation bifunctional anticancer agents.
B. Guan, Binbin Cheng, Hongqiao Li· Frontiers in Immunology· 0 citations
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