ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future Directions
<p>Ataxia-telangiectasia mutated (ATM) kinase plays a pivotal role in the cellular response to DNA damage. Under normal conditions, ATM acts as a tumor suppressor by regulating pathways that lead to apoptosis and cell cycle arrest via effectors like p53, p21, CHK1, and CHK2. Paradoxically, in...
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| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , , , , , , , |
| منشور في: |
2025
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| الموضوعات: | |
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إضافة وسم
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| _version_ | 1864513539896508416 |
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| author | Raed.M. Al-Zoubi (22254577) |
| author2 | Khalil Garada (22254580) Reem Al Huneidi (22254583) Zaid M.H. Baddar (22254586) Ayman A. Zarour (17917709) Mai Elaarag (17807390) Sally R. Al-Zoubi (22254589) Ahmad R. Al-Qudimat (17337808) Mazhar Salim Al Zoubi (18024364) Abdelali Agouni (181926) Khalid Alrumaihi (14779210) |
| author2_role | author author author author author author author author author author |
| author_facet | Raed.M. Al-Zoubi (22254577) Khalil Garada (22254580) Reem Al Huneidi (22254583) Zaid M.H. Baddar (22254586) Ayman A. Zarour (17917709) Mai Elaarag (17807390) Sally R. Al-Zoubi (22254589) Ahmad R. Al-Qudimat (17337808) Mazhar Salim Al Zoubi (18024364) Abdelali Agouni (181926) Khalid Alrumaihi (14779210) |
| author_role | author |
| dc.creator.none.fl_str_mv | Raed.M. Al-Zoubi (22254577) Khalil Garada (22254580) Reem Al Huneidi (22254583) Zaid M.H. Baddar (22254586) Ayman A. Zarour (17917709) Mai Elaarag (17807390) Sally R. Al-Zoubi (22254589) Ahmad R. Al-Qudimat (17337808) Mazhar Salim Al Zoubi (18024364) Abdelali Agouni (181926) Khalid Alrumaihi (14779210) |
| dc.date.none.fl_str_mv | 2025-09-12T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.ejmech.2025.118137 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/ATM_Inhibitors_in_Cancer_Radiotherapy_Mechanisms_Clinical_Development_and_Future_Directions/30135574 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences ATM inhibitors Radiotherapy Cancer therapy DNA damage response Clinical trials Translational |
| dc.title.none.fl_str_mv | ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future Directions |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>Ataxia-telangiectasia mutated (ATM) kinase plays a pivotal role in the cellular response to DNA damage. Under normal conditions, ATM acts as a tumor suppressor by regulating pathways that lead to apoptosis and cell cycle arrest via effectors like p53, p21, CHK1, and CHK2. Paradoxically, in some cancers, ATM promotes tumor cell survival and metastasis, especially when aberrantly activated, linking it to therapy resistance and poor outcomes. Its involvement in both radiotherapy and chemotherapy has made ATM an attractive target for cancer treatment. Inhibitors such as KU-55933, KU-60019, and AZD1390 have shown the potential to sensitize cancer cells to radiotherapy by impairing DNA repair, thereby enhancing treatment efficacy. A key challenge remains the development of ATM inhibitors that can effectively cross the blood-brain barrier for use against brain tumors. Currently, none have gained approval from the FDA or EMA, but six candidates, AZD1390, AZD0156, ZN-B-2262, SYH2051, WSD0628 and M3541 are in clinical trials, often as adjuncts to radiotherapy or in combination with PARP inhibitors. Their safety and effectiveness, however, are still under investigation. This review synthesizes ATM's dual roles and the therapeutic promise of targeting ATM in cancer radiotherapy.</p><h2>Other Information</h2> <p> Published in: European Journal of Medicinal Chemistry<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.ejmech.2025.118137" target="_blank">https://dx.doi.org/10.1016/j.ejmech.2025.118137</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_71b495dc026b84982a2c114819a554dd |
| identifier_str_mv | 10.1016/j.ejmech.2025.118137 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/30135574 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future DirectionsRaed.M. Al-Zoubi (22254577)Khalil Garada (22254580)Reem Al Huneidi (22254583)Zaid M.H. Baddar (22254586)Ayman A. Zarour (17917709)Mai Elaarag (17807390)Sally R. Al-Zoubi (22254589)Ahmad R. Al-Qudimat (17337808)Mazhar Salim Al Zoubi (18024364)Abdelali Agouni (181926)Khalid Alrumaihi (14779210)Biomedical and clinical sciencesOncology and carcinogenesisPharmacology and pharmaceutical sciencesATM inhibitorsRadiotherapyCancer therapyDNA damage responseClinical trialsTranslational<p>Ataxia-telangiectasia mutated (ATM) kinase plays a pivotal role in the cellular response to DNA damage. Under normal conditions, ATM acts as a tumor suppressor by regulating pathways that lead to apoptosis and cell cycle arrest via effectors like p53, p21, CHK1, and CHK2. Paradoxically, in some cancers, ATM promotes tumor cell survival and metastasis, especially when aberrantly activated, linking it to therapy resistance and poor outcomes. Its involvement in both radiotherapy and chemotherapy has made ATM an attractive target for cancer treatment. Inhibitors such as KU-55933, KU-60019, and AZD1390 have shown the potential to sensitize cancer cells to radiotherapy by impairing DNA repair, thereby enhancing treatment efficacy. A key challenge remains the development of ATM inhibitors that can effectively cross the blood-brain barrier for use against brain tumors. Currently, none have gained approval from the FDA or EMA, but six candidates, AZD1390, AZD0156, ZN-B-2262, SYH2051, WSD0628 and M3541 are in clinical trials, often as adjuncts to radiotherapy or in combination with PARP inhibitors. Their safety and effectiveness, however, are still under investigation. This review synthesizes ATM's dual roles and the therapeutic promise of targeting ATM in cancer radiotherapy.</p><h2>Other Information</h2> <p> Published in: European Journal of Medicinal Chemistry<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.ejmech.2025.118137" target="_blank">https://dx.doi.org/10.1016/j.ejmech.2025.118137</a></p>2025-09-12T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.ejmech.2025.118137https://figshare.com/articles/journal_contribution/ATM_Inhibitors_in_Cancer_Radiotherapy_Mechanisms_Clinical_Development_and_Future_Directions/30135574CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/301355742025-09-12T09:00:00Z |
| spellingShingle | ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future Directions Raed.M. Al-Zoubi (22254577) Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences ATM inhibitors Radiotherapy Cancer therapy DNA damage response Clinical trials Translational |
| status_str | publishedVersion |
| title | ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future Directions |
| title_full | ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future Directions |
| title_fullStr | ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future Directions |
| title_full_unstemmed | ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future Directions |
| title_short | ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future Directions |
| title_sort | ATM Inhibitors in Cancer Radiotherapy: Mechanisms, Clinical Development, and Future Directions |
| topic | Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences ATM inhibitors Radiotherapy Cancer therapy DNA damage response Clinical trials Translational |