Targeting DNA-PK: medicinal chemistry insights into small-molecule inhibitor discovery and optimisation

Elle Watson; Jack R. R. Hutchinson; Suzannah J. Harnor; Luke Gaughan; Céline Cano

doi:10.1039/d6md00119j

January 1, 2026RSC Medicinal Chemistry

Targeting DNA-PK: medicinal chemistry insights into small-molecule inhibitor discovery and optimisation

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Key Points

This review aims to provide insights into the discovery and optimization of DNA-PK inhibitors for therapeutic use.
Reviewed the synthesis of DNA-PK inhibitors from early hits to clinical candidates.
Discussed the pharmacological profiles of optimized scaffolds like chromen-4-ones and purinones.
Highlighted the advancements in DNA-PK inhibitor development since Wortmannin.
Provided examples of optimized inhibitors such as NU5455 and AZD7648.

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Implication

Review highlights the discovery and optimization of DNA-PK inhibitors, indicating their potential in treatment.

Abstract

Since Wortmannin's discovery, DNA-PK inhibitors have expanded to optimised scaffolds, including chromen-4-ones ( e.g. NU5455) and purinones ( e.g. AZD7648). This review covers their synthesis and pharmacology from early hits to clinical candidates.

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Watson et al. (2026) studied this question.

synapsesocial.com/papers/6a28fecb6f82f25be989c068 https://doi.org/10.1039/d6md00119j

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Targeting DNA-PK: medicinal chemistry insights into small-molecule inhibitor discovery and optimisation

Key Points

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Implication

Abstract

Discussion

Cite This Study

Targeting DNA-PK: medicinal chemistry insights into small-molecule inhibitor discovery and optimisation

Key Points

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Implication

Abstract

Discussion

Cite This Study

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