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Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma
Ying-Qi Feng1, Shuang-Xi Gu1, Yong-Shou Chen1
1Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430072, People's Republic of China.
Background:
Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC.
Methods:
A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound (2a) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described.
Results:
The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound 2a, with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC50=7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα. Moreover, 2a significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner.
Conclusion:
A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTOR-specific inhibitors for use as radiosensitizers for HCC radiotherapy.
Insights
Researchers developed a new selective mammalian target of rapamycin (mTOR) inhibitor, compound 2a, to overcome radiotherapy resistance in hepatocellular carcinoma (HCC). This compound enhances HCC
Area of Science:
- Medicinal Chemistry
- Oncology
- Radiotherapy
Background:
- Hepatocellular carcinoma (HCC) exhibits resistance to radiotherapy.
- Overactivated mammalian target of rapamycin (mTOR) signaling contributes to this radioresistance.
- Targeting mTOR presents a potential strategy to enhance HCC radiotherapy efficacy.
Purpose of the Study:
- To develop novel selective inhibitors of mTOR.
- To investigate the radiosensitizing potential of these inhibitors in HCC.
Main Methods:
- Pharmacophore modeling and molecular docking were used to identify and optimize lead compounds.
- Compound 2a was synthesized and characterized.
- In vitro radiosensitizing effects were evaluated using colony formation and DNA double-strand break assays.
Main Results:
- Compound 2a, a selective mTOR inhibitor, demonstrated potent inhibition of mTOR (IC50=7.1 nM) with high selectivity over PI3Kα.
- Compound 2a significantly enhanced the radiosensitivity of HCC cells in a dose-dependent manner.
- Preclinical characteristics of compound 2a were established.
Conclusions:
- A new class of selective mTOR inhibitors with confirmed radiosensitization effects was developed.
- Compound 2a shows promise as a radiosensitizer for HCC radiotherapy.
- This study provides a foundation for developing mTOR-specific inhibitors for clinical application in HCC treatment.
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