Related Experiment Video
Updated: Dec 29, 2025
A High-Throughput Enzyme-Coupled Activity Assay to Probe Small Molecule Interaction with the dNTPase SAMHD1
Published on: April 16, 2021
Discovery of Novel Inhibitors Targeting Multi-UDP-hexose Pyrophosphorylases as Anticancer Agents
Yueqin Yang1, Hariprasad Vankayalapati2,3, Manshu Tang1
1Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
Abstract:
To minimize treatment toxicities, recent anti-cancer research efforts have switched from broad-based chemotherapy to targeted therapy, and emerging data show that altered cellular metabolism in cancerous cells can be exploited as new venues for targeted intervention. In this study, we focused on, among the altered metabolic processes in cancerous cells, altered glycosylation due to its documented roles in cancer tumorigenesis, metastasis and drug resistance. We hypothesize that the enzymes required for the biosynthesis of UDP-hexoses, glycosyl donors for glycan synthesis, could serve as therapeutic targets for cancers. Through structure-based virtual screening and kinetic assay, we identified a drug-like chemical fragment, GAL-012, that inhibit a small family of UDP-hexose pyrophosphorylases-galactose pyro-phosphorylase (GALT), UDP-glucose pyrophosphorylase (UGP2) and UDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1) with an IC50 of 30 µM. The computational docking studies supported the interaction of GAL-012 to the binding sites of GALT at Trp190 and Ser192, UGP2 at Gly116 and Lys127, and AGX1/UAP1 at Asn327 and Lys407, respectively. One of GAL-012 derivatives GAL-012-2 also demonstrated the inhibitory activity against GALT and UGP2. Moreover, we showed that GAL-012 suppressed the growth of PC3 cells in a dose-dependent manner with an EC50 of 75 µM with no effects on normal skin fibroblasts at 200 µM. Western blot analysis revealed reduced expression of pAKT (Ser473), pAKT (Thr308) by 77% and 72%, respectively in the treated cells. siRNA experiments against the respective genes encoding the pyrophosphorylases were also performed and the results further validated the proposed roles in cancer growth inhibition. Finally, synergistic relationships between GAL-012 and tunicamycin, as well as bortezomib (BTZ) in killing cultured cancer cells were observed, respectively. With its unique scaffold and relatively small size, GAL-012 serves as a promising early chemotype for optimization to become a safe, effective, multi-target anti-cancer drug candidate which could be used alone or in combination with known therapeutics.
Insights
Researchers identified GAL-012, a novel fragment inhibiting key enzymes in cancer cell glycosylation and growth. This targeted therapy shows promise for developing new anti-cancer drugs, alone or with existing treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Shift from chemotherapy to targeted therapies to minimize toxicity.
- Altered cellular metabolism, particularly glycosylation, is a hallmark of cancer.
- Glycosylation plays critical roles in tumorigenesis, metastasis, and drug resistance.
Purpose of the Study:
- To investigate UDP-hexose pyrophosphorylases as potential therapeutic targets in cancer.
- To identify and characterize novel inhibitors of these enzymes.
- To evaluate the anti-cancer efficacy and safety of identified compounds.
Main Methods:
- Structure-based virtual screening and kinetic assays to identify inhibitors.
- Computational docking studies to predict binding interactions.
- Cell-based assays (growth inhibition, Western blot, siRNA) to assess efficacy and mechanism.
- Combination studies with known anti-cancer drugs.
Main Results:
- Identification of GAL-012, a chemical fragment inhibiting UDP-hexose pyrophosphorylases (GALT, UGP2, AGX1/UAP1) with IC50 of 30 µM.
- GAL-012 suppressed PC3 cancer cell growth (EC50 of 75 µM) without affecting normal fibroblasts.
- Observed synergistic effects of GAL-012 with tunicamycin and bortezomib in killing cancer cells.
Conclusions:
- Targeting UDP-hexose pyrophosphorylases offers a novel strategy for cancer intervention.
- GAL-012 is a promising chemotype for developing multi-target anti-cancer drugs.
- GAL-012 demonstrates potential for use as a standalone or combination therapy.
More Related Videos
08:49Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
13:35Structural Biology and Analytical Chemistry Approaches for Characterizing C-Glycoside Metabolic Enzymes in Human Gut Microbiota
Published on: May 23, 2025
