The structure-activity relationship study of torkinib derivatives as mTOR inhibitors with senolytic and STAT3
Patrik Oleksak1, David Rysanek2, Marketa Vancurova2
1Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 50003 Hradec Kralove, Czech Republic.
Abstract:
The mechanistic target of rapamycin (mTOR) sits at the center of several cellular pathways determining cell growth, function, and stress adaptation. Dysregulated mTOR signaling contributes to aging-related diseases and cancer, making mTOR inhibitors an important class of anticancer therapeutics. Likewise, STAT3 is a transcription factor that drives cell proliferation and survival, and its hyperactivation is implicated in many cancers. As a result, STAT3 inhibitors also represent a promising group of anticancer compounds. This study describes the synthesis and characterization of 10 heteroarene derivatives of torkinib, a known mTOR inhibitor. We evaluated these compounds for their mTOR and STAT3 inhibitory activities, growth inhibitory and senolytic effects. A structure-activity relationship (SAR) study and molecular docking analysis were conducted to elucidate key structural features. Notably, torkinib derivative 4k demonstrated potent mTOR inhibition without affecting STAT3 phosphorylation, whereas its analog 4j inhibited phosphorylation of both mTOR and STAT3. Furthermore, compared to compound 4j, compound 4k exhibited cytotoxicity against both proliferating and senescent cells, comparable to torkinib despite its weaker TORC1 inhibition. In conclusion, our findings reveal structural alignments crucial for enhanced mTOR and STAT3 inhibition.
Insights
New torkinib derivatives show promise as anticancer agents. Compound 4k potently inhibits mTOR, while 4j targets both mTOR and STAT3, offering potential for novel cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- The mechanistic target of rapamycin (mTOR) and STAT3 signaling pathways are crucial for cell growth and survival.
- Dysregulation of mTOR and STAT3 is implicated in aging-related diseases and various cancers.
- mTOR inhibitors and STAT3 inhibitors are vital anticancer therapeutic strategies.
Purpose of the Study:
- To synthesize and characterize novel heteroarene derivatives of torkinib, a known mTOR inhibitor.
- To evaluate these derivatives for their inhibitory effects on mTOR and STAT3.
- To explore their potential as anticancer agents through growth inhibition and senolytic activity assessments.
Main Methods:
- Synthesis and characterization of 10 heteroarene derivatives of torkinib.
- In vitro evaluation of mTOR and STAT3 inhibitory activities.
- Structure-activity relationship (SAR) studies and molecular docking analyses.
- Assessment of cytotoxicity against proliferating and senescent cells.
Main Results:
- Torkinib derivative 4k showed potent mTOR inhibition without affecting STAT3 phosphorylation.
- Analog 4j inhibited phosphorylation of both mTOR and STAT3.
- Compound 4k demonstrated significant cytotoxicity against both proliferating and senescent cells, comparable to torkinib.
- SAR and docking studies identified key structural features for enhanced inhibition.
Conclusions:
- Novel torkinib derivatives possess significant mTOR and/or STAT3 inhibitory activities.
- Specific structural features are crucial for achieving potent and selective inhibition of these pathways.
- These compounds represent promising leads for the development of new anticancer therapeutics targeting mTOR and STAT3 signaling.
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