Jul 2026· Journal of Medicinal Chemistry· Vol 69, pp. 19018-19049· 0 citations· 39 references
Medicine
Abstract
Metabolic reprogramming relying on abnormal glycolysis fuels tumor growth, rendering the rate-limiting glycolytic enzyme PFKL a potential anticancer target; yet no PFKL inhibitor has entered clinical trials. Herein, we synthesized a series of S-benzylisothiourea imidazolium salt derivatives and identified compound 10w, which potently inhibited breast cancer cell proliferation, suppressed glycolysis, and induced apoptosis. Drug Affinity Responsive Target Stability (DARTS) assays revealed PFKL as the direct cellular target of 10w. Surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and molecular docking studies confirmed the binding of 10w to PFKL. Enzymatic activity assays further demonstrated that 10w inhibited PFKL activity. Notably, 10w exerted no obvious effects on glycolysis or glycolytic capacity in PFKL-knockdown breast cancer cells. In vivo assays showed that 10w exerted significant antitumor efficacy and enhanced the efficacy of anti-PD-L1 immunotherapy. In conclusion, compound 10w targets PFKL as a promising therapeutic agent for breast cancer.
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 antitumor activity of three levoglucosenone-based derivatives in preclinical breast cancer models demonstrated that two of the derivatives significantly inhibited tumor growth and metastatic dissemination without evidence of systemic toxicity, indicating a promising synergistic effect.
Luciana Cañonero, Aldana M. Schey, Lizeth Ariza Bareño et al.· European Journal of Pharmaco...· 0 citations
The findings demonstrate that indole-benzimidazole hybrids function as multifunctional modulators of breast cancer cell metabolism by coordinately targeting lipid homeostasis, sphingolipid-associated signaling, autophagic regulation, and apoptosis.
E. Acikgoz, Mustafa Çakır, B. Kuzu· Naunyn-Schmiedeberg's Archiv...· 0 citations
The glycoconjugate ligand induces apoptosis and cell cycle arrest through oxidative and metabolic stress mediated by AMPK–STK11 signaling, highlighting its potential as a GLUT-targeted chemotherapeutic agent for breast cancer treatment.
Safaa S. Hassan, Fatma B. Rashidi, Ramy G. Seddik et al.· Scientific Reports· 0 citations
Ovarian cancer (OC) cells promote rapid proliferation via aerobic glycolysis and build an immunosuppressive microenvironment at the same time; therefore, this glycolytic pathway is now a potential drug target. Existing glycolysis inhibitors are limited by off-target toxicity, drug resistance, and variable efficacy acro...
Hong-Li Lv, Xi Jiang, Wei Zhang et al.· Frontiers in Pharmacology· 0 citations
This work identifies YM17 as a potent sophoridine-derived TNIK inhibitor with cellular target engagement and in vivo anti-HCC activity and highlights the value of integrating phenotype-guided natural product scaffold diversification with proteome-scale target deconvolution for anticancer lead discovery.
Yong-Quan Wei, Zi-Yi Wang, Die Sun et al.· European journal of medicina...· 0 citations
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