Discovery of novel ataxia telangiectasia mutated (ATM) kinase modulators: Computational simulation, biological
Xiaodong Dou1, Xiaojiao Sun2, Huixia Huang3
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China.
Abstract:
Ataxia-telangiectasia mutated (ATM) kinase is a serine/threonine protein kinase and plays a key role in DNA double-strand breaks repair. Thus, ATM is considered a promising target for radiotherapy and chemotherapy sensitizing. Herein, we report the discovery of ATM agonist A22 and inhibitor A41 by computational methods and further biological evaluation. Among them, A22 exhibited low cytotoxicity in vitro and might serve as a useful tool for ATM research. Moreover, we firstly proved that ATM inhibitors could sensitize Irinotecan and Etoposide in a time-dependent manner on MCF-7 and SW480 cells, antagonism in a short period treatment while synergy at a long-term treatment and ATM agonist worked in an opposite way of ATM inhibitors. Further mechanism study demonstrated that the antagonism effect of ATM inhibitors with chemotherapeutic agents in a short period was resulting from inhibiting the p53/p21 axis to accelerate G1/S phase cell-cycle transition and promote cell survival. Additionally, A41 displayed antitumor effects combined with a chemotherapeutic drug in the SW480 xenograft model, indicating that A41 is a promising ATM inhibitor, which could increase the antitumor effect of chemotherapeutic drugs in vivo. All in all, these findings will guide the combination of ATM inhibitors with chemotherapeutic agents in further preclinical and clinical studies.
Insights
Researchers discovered ATM agonist A22 and inhibitor A41. ATM inhibitors sensitize chemotherapy drugs like Irinotecan and Etoposide, showing synergy in long-term treatment, while the agonist has opposite effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Ataxia-telangiectasia mutated (ATM) kinase is crucial for DNA double-strand break repair.
- ATM is a potential target for enhancing radiotherapy and chemotherapy efficacy.
Purpose of the Study:
- To discover and evaluate novel ATM modulators (agonist A22, inhibitor A41).
- To investigate the role of ATM modulation in sensitizing cancer cells to chemotherapy.
- To explore the underlying mechanisms of ATM inhibitor and agonist actions.
Main Methods:
- Computational methods for drug discovery.
- In vitro cytotoxicity assays.
- Cell-cycle analysis.
- In vivo xenograft studies.
Main Results:
- ATM agonist A22 showed low in vitro cytotoxicity.
- ATM inhibitors demonstrated time-dependent sensitization of MCF-7 and SW480 cells to Irinotecan and Etoposide, with antagonism in short-term and synergy in long-term treatments.
- ATM inhibitors, by inhibiting the p53/p21 axis, accelerate G1/S phase transition, promoting cell survival in short-term treatment.
- ATM agonist exhibited opposite effects compared to inhibitors.
- In vivo, A41 combined with chemotherapy showed antitumor effects in a SW480 xenograft model.
Conclusions:
- A22 is a valuable tool for ATM research.
- ATM inhibitors can be combined with chemotherapeutic agents for enhanced antitumor effects, particularly in long-term treatments.
- A41 is a promising ATM inhibitor for preclinical and clinical studies to improve chemotherapy outcomes.
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