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Review
. 2025 Dec;40(1):2489720.
doi: 10.1080/14756366.2025.2489720. Epub 2025 Apr 21.

Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics

Ram Sharma  1 , Anshul Mishra  1 , Monika Bhardwaj  2 , Gurpreet Singh  3 , Larasati Vanya Indira Harahap  1 , Sakshi Vanjani  4 , Chun Hsu Pan  5 , Kunal Nepali  1   5
Affiliations
Review

Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics

Ram Sharma et al. J Enzyme Inhib Med Chem. 2025 Dec.

Abstract

This review discusses the critical roles of Ataxia Telangiectasia Mutated Kinase (ATM), ATM and Rad3-related Kinase (ATR), and DNA-dependent protein kinase (DNA-PK) in the DNA damage response (DDR) and their implications in cancer. Emphasis is placed on the intricate interplay between these kinases, highlighting their collaborative and distinct roles in maintaining genomic integrity and promoting tumour development under dysregulated conditions. Furthermore, the review covers ongoing clinical trials, patent literature, and medicinal chemistry campaigns on ATM/ATR/DNA-PK inhibitors as antitumor agents. Notably, the medicinal chemistry campaigns employed robust drug design strategies and aimed at assembling new structural templates with amplified DDR kinase inhibitory ability, as well as outwitting the pharmacokinetic liabilities of the existing DDR kinase inhibitors. Given the success attained through such endeavours, the clinical pipeline of DNA repair kinase inhibitors is anticipated to be supplemented by a reasonable number of tractable entries (DDR kinase inhibitors) soon.

Keywords: ATM and Rad3-related kinase; Ataxia Telangiectasia Mutated; DNA damage; DNA-PK; cancer.

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Conflict of interest statement

Kunal Nepali is an associated editor of the Journal of Enzyme Inhibition and Medicinal Chemistry. There is no other potential conflict of interest to be declared by the authors.

Figures

Figure 1.
Figure 1.
Closed dimeric structure of Ataxia Telangiectasia Mutated (ATM) (the figure was drawn by the authors using BioRender software).
Figure 2.
Figure 2.
Mechanism of ATM kinase activation in DNA double strand (the figure was drawn by the authors using BioRender software).
Figure 3.
Figure 3.
(a) Dimeric structure of ATR protein and (b) activation of ATR for DNA single strand damage (the figure was drawn by the authors using BioRender software).
Figure 4.
Figure 4.
(a) Dimeric structure of DNA-PK and (b) DNA repair mechanism of DNA-PK (the figure was drawn by the authors using BioRender software).
Figure 5.
Figure 5.
Quinoline carboxamides as ATM inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 6.
Figure 6.
Cinnoline carboxamides based selective ATM inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 7.
Figure 7.
Discovery of first-in-class AZD0156 as ATM kinase inhibitor (the figure was drawn by the authors using Chemdraw software).
Figure 8.
Figure 8.
Development of novel urea-based ATM kinase inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 9.
Figure 9.
Discovery of novel ATM kinase modulators (the figure was drawn by the authors using Chemdraw software).
Figure 10.
Figure 10.
Novel benzimidazole and Imidazo[4,5-b]pyridine-based ATM kinase inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 11.
Figure 11.
Quinoxalin urea derivatives as ATM inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 12.
Figure 12.
Discovery of novel AZD1390 (7) as an ATM kinase inhibitor with BBB permeability (the figure was drawn by the authors using Chemdraw software).
Figure 13.
Figure 13.
Meisoindigo-derived PROTAC as the ATM degrader (the figure was drawn by the authors using Chemdraw software).
Figure 14.
Figure 14.
Development of potent and selective ATM and Rad3-related ATR kinase inhibitor (the figure was drawn by the authors using Chemdraw software).
Figure 15.
Figure 15.
Discovery of potent and selective ATR inhibitor (AZ20) (the figure was drawn by the authors using Chemdraw software).
Figure 16.
Figure 16.
Discovery of pyrimidine based as ATR inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 17.
Figure 17.
Discovery of the novel potent and selective ATR inhibitor camonsertib (the figure was drawn by the authors using Chemdraw software).
Figure 18.
Figure 18.
Discovery of potent ATR inhibitor (AD1058) (the figure was drawn by the authors using Chemdraw software).
Figure 19.
Figure 19.
Discovery of novel potent ATM and Rad3-related ATR kinase inhibitor (the figure was drawn by the authors using Chemdraw software).
Figure 20.
Figure 20.
Discovery of potent and selective Thieno[3,2-d]pyrimidine derivatives (the figure was drawn by the authors using Chemdraw software).
Figure 21.
Figure 21.
Discovery of new potent and selective tetrahydropyrazolo [1,5‑a]pyrazines as ATR Inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 22.
Figure 22.
Discovery of potent azabenzimidazoles based as ATR inhibitor (the figure was drawn by the authors using Chemdraw software).
Figure 23.
Figure 23.
Discovery of first in class (VX-970, M6620) as ATR inhibitor (the figure was drawn by the authors using Chemdraw software).
Figure 24.
Figure 24.
Discovery of BAY-1895344 as an orally active, selective, and potent ATR inhibitor (the figure was drawn by the authors using Chemdraw software).
Figure 25.
Figure 25.
Discovery of highly selected ATR kinase inhibitor (the figure was drawn by the authors using Chemdraw software).
Figure 26.
Figure 26.
Discovery of the first Ataxia Telangiectasia and Rad3-related (ATR-PROTAC) (the figure was drawn by the authors using Chemdraw software).
Figure 27.
Figure 27.
Discovery of novel first-in-class proteolysis targeting chimaera (PROTACs) (the figure was drawn by the authors using Chemdraw software).
Figure 28.
Figure 28.
Chromen-4-one based DNA-dependent protein kinase (DNA-PK) inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 29.
Figure 29.
Discovery of pyridopyrimidin-4-one derivatives based DNA-PK inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 30.
Figure 30.
Discovery of benzopyranone-based DNA-pk inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 31.
Figure 31.
Novel series of benzoxazine-based compounds for DNA-PK inhibitor (the figure was drawn by the authors using Chemdraw software).
Figure 32.
Figure 32.
Discovery of dual DNA-PK and PI3K inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 33.
Figure 33.
Discovery of AZD7648 potent and selective DNA-PK inhibitor (the figure was drawn by the authors using Chemdraw software).
Figure 34.
Figure 34.
Discovery of 7,8-dihydropteridine-6(5H) based DNA-PK inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 35.
Figure 35.
Discovery of heterotricyclic based as DNA-dependent kinase (DNA-PK) inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 36.
Figure 36.
Discovery of AZD7648 derivative as DNA-PK inhibitors (the figure was drawn by the authors using Chemdraw software).
Figure 37.
Figure 37.
Discovery of potential antitumor agent as DNA-PK inhibitor for conjugated therapy (the figure was drawn by the authors using Chemdraw software).
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