Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy

International Journal of Molecular Sciences

卷:23

Yoshihisa Matsumoto¹ 

[1] Laboratory for Zero-Carbon Energy, Institute of Innovative Research, Tokyo Institute of Technology, Tokyo 152-8550, Japan;

关键词: DNA double-strand break (DSB);    non-homologous end joining (NHEJ);    DNA-dependent protein kinase (DNA-PK);    phosphatidylinositol 3-kinase;    inhibitor;    radiosensitization;   

DOI  :  10.3390/ijms23084264

来源: DOAJ

【 摘 要 】

DNA double-strand break (DSB) is considered the most deleterious type of DNA damage, which is generated by ionizing radiation (IR) and a subset of anticancer drugs. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a pivotal role in DSB repair through non-homologous end joining (NHEJ). Cells deficient for DNA-PKcs show hypersensitivity to IR and several DNA-damaging agents. Cellular sensitivity to IR and DNA-damaging agents can be augmented by the inhibition of DNA-PK. A number of small molecules that inhibit DNA-PK have been developed. Here, the development and evolution of inhibitors targeting DNA-PK for cancer therapy is reviewed. Significant parts of the inhibitors were developed based on the structural similarity of DNA-PK to phosphatidylinositol 3-kinases (PI3Ks) and PI3K-related kinases (PIKKs), including Ataxia-telangiectasia mutated (ATM). Some of DNA-PK inhibitors, e.g., NU7026 and NU7441, have been used extensively in the studies for cellular function of DNA-PK. Recently developed inhibitors, e.g., M3814 and AZD7648, are in clinical trials and on the way to be utilized in cancer therapy in combination with radiotherapy and chemotherapy.

【 授权许可】

Unknown