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Benzothiazole and Chromone Derivatives as Potential ATR Kinase Inhibitors and Anticancer Agents
Mykhaylo Frasinyuk1, Dimple Chhabria2, Victor Kartsev3
1V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, 02094 Kiev, Ukraine.
Abstract:
Despite extensive studies and the great variety of existing anticancer agents, cancer treatment remains an aggravating and challenging problem. Therefore, the development of novel anticancer drugs with a better therapeutic profile and fewer side effects to combat this persistent disease is still necessary. In this study, we report a novel series of benzothiazole and chromone derivatives that were synthesized and evaluated for their anticancer activity as an inhibitor of ATR kinase, a master regulator of the DDR pathway. The cell viability of a set of 25 compounds was performed using MTT assay in HCT116 and HeLa cell lines, involving 72 h incubation of the compounds at a final concentration of 10 µM. Cells incubated with compounds 2c, 7h and 7l were found to show viability ≤50%, and were taken forward for dose-response studies. Among the tested compounds, three of them (2c, 7h and 7l) showed higher potency, with compound 7l exhibiting the best IC50 values in both the cell lines. Compounds 2c and 7l were found to be equally cytotoxic towards both the cell lines, namely, HCT116 and HeLa, while compound 7h showed better cytotoxicity towards HeLa cell line. For these three compounds, an immunoblot assay was carried out in order to analyze the inhibition of phosphorylation of Chk1 at Ser 317 in HeLa and HCT116 cells. Compound 7h showed inhibition of pChk1 at Ser 317 in HeLa cells at a concentration of 3.995 µM. Further analysis for Chk1 and pChk1 expression was carried out in Hela cells by treatment against all the three compounds at a range of concentrations of 2, 5 and 10 µM, wherein compound 7h showed Chk1 inhibition at 2 and 5 µM, while pChk1 expression was observed for compound 7l at a concentration of 5 µM. To support the results, the binding interactions of the compounds with the ATR kinase domain was studied through molecular docking, wherein compounds 2c, 7h and 7l showed binding interactions similar to those of Torin2, a known mTOR/ATR inhibitor. Further studies on this set of molecules is in progress for their specificity towards the ATR pathway.
Insights
Researchers developed new benzothiazole and chromone derivatives as potential anticancer drugs targeting ATR kinase. Compounds 7l, 2c, and 7h demonstrated significant anticancer activity and warrant further investigation.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Cancer remains a significant global health challenge, necessitating the development of novel therapeutic agents.
- Existing treatments often face limitations such as side effects and resistance, highlighting the need for innovative anticancer drugs.
- Targeting key regulators of DNA damage response (DDR) pathways, like ATR kinase, presents a promising strategy for cancer therapy.
Purpose of the Study:
- To synthesize and evaluate a novel series of benzothiazole and chromone derivatives for their anticancer potential.
- To identify potent inhibitors of ATR kinase, a crucial enzyme in the DNA damage response pathway.
- To assess the cytotoxicity and mechanism of action of promising compounds in relevant cancer cell lines.
Main Methods:
- Synthesis of novel benzothiazole and chromone derivatives.
- MTT cytotoxicity assays were performed on HCT116 and HeLa cancer cell lines at a fixed concentration (10 µM) and for dose-response studies.
- Immunoblot assays were used to analyze the inhibition of Chk1 phosphorylation (pChk1) at Ser 317.
- Molecular docking studies were conducted to investigate binding interactions with the ATR kinase domain.
Main Results:
- Twenty-five compounds were synthesized and screened; compounds 2c, 7h, and 7l exhibited significant cytotoxicity (viability ≤50%).
- Compound 7l demonstrated the most potent IC50 values across both HCT116 and HeLa cell lines.
- Compounds 7h and 7l effectively inhibited Chk1 phosphorylation, a downstream target of ATR kinase, with compound 7h showing inhibition at 3.995 µM in HeLa cells.
- Molecular docking revealed binding interactions of compounds 2c, 7h, and 7l within the ATR kinase domain, comparable to the known inhibitor Torin2.
Conclusions:
- Novel benzothiazole and chromone derivatives show promising anticancer activity through ATR kinase inhibition.
- Compounds 2c, 7h, and 7l are identified as lead candidates for further development as ATR kinase inhibitors.
- These findings support the potential of targeting the DDR pathway with novel small molecules for cancer treatment.
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