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Published on: August 2, 2024
A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3
Xiaofei Shen1, Lin Zhao1, Peihao Chen2,3
1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Abstract:
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in ∼70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy. However, specific direct STAT3 inhibitors remain to be developed. Oridonin is an ent-kaurane plant-derived diterpenoid with anti-cancer and anti-inflammatory activities. Here, using an array of cell-based and biochemical approaches, including cell proliferation and apoptosis assays, pulldown and reporter gene assays, site-directed mutagenesis, and molecular dynamics analyses, we report that a thiazole-derived oridonin analogue, CYD0618, potently and directly inhibits STAT3. We found that CYD0618 covalently binds to Cys-542 in STAT3 and suppresses its activity through an allosteric effect, effectively reducing STAT3 dimerization and nuclear translocation, as well as decreasing expression of STAT3-targeted oncogenes. Remarkably, CYD0618 not only strongly inhibited growth of multiple cancer cell lines that harbor constitutive STAT3 activation, but it also suppressed in vivo tumor growth via STAT3 inhibition. Taken together, our findings suggest Cys-542 as a druggable site for selectively inhibiting STAT3 and indicate that CYD0618 represents a promising lead compound for developing therapeutic agents against STAT3-driven diseases.
Insights
A novel compound, CYD0618, directly inhibits signal transducer and activator of transcription 3 (STAT3) by covalently binding to Cys-542. This inhibition suppresses cancer cell growth and tumor development, offering a promising therapeutic strategy for STAT3-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is prevalent in human cancers.
- STAT3 is a key therapeutic target, but specific inhibitors are lacking.
- Oridonin, a plant-derived compound, exhibits anti-cancer properties.
Purpose of the Study:
- To identify and characterize a novel, direct inhibitor of STAT3.
- To evaluate the anti-cancer efficacy of the identified inhibitor.
- To explore the mechanism of action for STAT3 inhibition.
Main Methods:
- Cell-based assays (proliferation, apoptosis)
- Biochemical assays (pulldown, reporter gene)
- Site-directed mutagenesis
- Molecular dynamics analyses
- In vivo tumor growth studies
Main Results:
- A thiazole-derived oridonin analogue, CYD0618, was identified as a potent STAT3 inhibitor.
- CYD0618 covalently binds to Cys-542 in STAT3, causing allosteric inhibition.
- Inhibition of STAT3 by CYD0618 reduced STAT3 dimerization, nuclear translocation, and oncogene expression.
- CYD0618 suppressed the growth of STAT3-activated cancer cell lines and inhibited tumor growth in vivo.
Conclusions:
- Cys-542 is a druggable site for selective STAT3 inhibition.
- CYD0618 is a promising lead compound for developing therapeutics against STAT3-driven diseases.
- Targeting STAT3 with CYD0618 offers a potential therapeutic strategy for various cancers.
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