Chapter 6 - Emerging small-molecule inhibitors of ATM kinase targeting cancer therapy

Abstract

Ataxia-Telangiectasia Mutated (ATM) is a serine-threonine kinase that activates checkpoint signaling, leading to dsDNA breaks (DSBs), cell death, and acts as a DNA damage sensor. ATMs belong to a large family of phosphatidylinositol 3-kinase (PIKKs) that are involved in cell growth and division. Ataxia-telangiectasia is a rare human disease characterized by cerebellar deterioration, excessive cellular sensitivity toward dissemination, and a disposition to carcinoma caused by a mutation in the ATM gene. A rapid increase in the kinase activity at the time of double-strand break was observed and considered an attractive drug target. Structurally, ATM consists of a proline-rich region and a leucine zipper, which helps in the DNA binding. This protein shows a significant starring role in the steady growth and the immune and nervous system activities. Here, we aimed to provide a comprehensive knowledge of different aspects of ATM, including regulation, function, mechanisms of action in different diseases, with a special focus on the therapeutic implication in the clinical trial of various cancer. This chapter further deals with a comprehensive understanding of the functioning of ATM kinase and its role in disease development. In addition, our main focus is to highlight structural features of ATM kinase, which could be implicated in the design and development of small-molecule inhibitors and their consequential impact on human health. The analysis of disease association will be helpful in understanding the underlying mechanism and thus helps in the development of effective inhibitors their implication in targeting anti-cancer therapeutics.