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Updated: May 2, 2026
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
High-throughput screening identifies a dual-activity inhibitor of OXCT1 for hepatocellular carcinoma therapy
Rui Liu1, Yuchen Sun1, Shengqi Shen2
1State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China; Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
Abstract:
3-Oxoacid CoA-transferase 1 (OXCT1) plays a crucial role in hepatocellular carcinoma (HCC) progression through its ketolytic and succinyltransferase activities. Despite its potential as a therapeutic target, no small molecules have been developed to inhibit the dual enzymatic activities of OXCT1 specifically. In this study, our structural analysis revealed that the active sites for both enzymatic functions of OXCT1 are located in the same pocket. Targeting this pocket inhibits the binding of OXCT1 to its substrates and blocks both of its enzymatic activities. Thus, we developed two high-throughput screening systems to assess the effects of small molecules on OXCT1's distinct enzymatic activities. By combining these experimental approaches with virtual screening, we identified a compound, D574-0246 (iOXCT1), which effectively inhibits both enzymatic activities. In vitro and in vivo validation demonstrated that iOXCT1 suppresses HCC growth via OXCT1 inhibition. Collectively, our results establish OXCT1 as a promising therapeutic target and identify iOXCT1 as a novel dual-activity inhibitor, providing a foundation for developing OXCT1-targeted therapies against HCC.
Insights
Researchers identified a novel dual-activity inhibitor, iOXCT1, targeting 3-Oxoacid CoA-transferase 1 (OXCT1). This compound effectively suppresses hepatocellular carcinoma (HCC) growth by blocking OXCT1
Area of Science:
- Biochemistry
- Oncology
- Drug Discovery
Background:
- 3-Oxoacid CoA-transferase 1 (OXCT1) is implicated in hepatocellular carcinoma (HCC) progression.
- OXCT1 possesses dual ketolytic and succinyltransferase activities crucial for HCC.
- No specific small molecule inhibitors targeting both OXCT1 activities exist.
Purpose of the Study:
- To identify small molecules that inhibit both enzymatic activities of OXCT1.
- To explore OXCT1 as a therapeutic target for HCC.
Main Methods:
- Structural analysis to locate OXCT1 active sites.
- Development of high-throughput screening systems for OXCT1 enzymatic activities.
- Virtual screening and experimental validation of identified compounds.
Main Results:
- The active sites for both OXCT1 enzymatic functions reside in the same pocket.
- A novel dual-activity inhibitor, D574-0246 (iOXCT1), was identified.
- iOXCT1 demonstrated efficacy in suppressing HCC growth both in vitro and in vivo.
Conclusions:
- OXCT1 is a promising therapeutic target for HCC.
- iOXCT1 is a novel inhibitor with dual activity against OXCT1.
- This study provides a foundation for developing OXCT1-targeted HCC therapies.
