Discovery of novel ataxia telangiectasia mutated (ATM) kinase modulators: Computational simulation, biological evaluation and cancer combinational chemotherapy study

Eur J Med Chem. 2022 Apr 5:233:114196. doi: 10.1016/j.ejmech.2022.114196.

Xiaodong Dou ¹, Xiaojiao Sun ², Huixia Huang ³, Lan Jiang ², Zefang Jin ², Yameng Liu ², Yang Zou ², Zhongtang Li ², Guiwang Zhu ², Hongwei Jin ², Ning Jiao ², Liangren Zhang ⁴, Zhenming Liu ⁵, Lihe Zhang ²

Affiliations

1 State 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.
2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.
4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: liangren@bjmu.edu.cn.
5 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: zmliu@bjmu.edu.cn.

PMID: 35231830 DOI: 10.1016/j.ejmech.2022.114196

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.

Keywords

ATM agonist; ATM inhibitor; Chemotherapeutic agents; Drug combination; Time-dependent manner.

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