Send Orders for Reprints to reprints@benthamscience.net Mini-Reviews in Medicinal Chemistry, 2014, 14, 805-811 805 The Development of Ataxia Telangiectasia Mutated Kinase Inhibitors Martin Andrs 1,2 , Jan Korabecny 1,2 , Eugenie Nepovimova 1,2 , Daniel Jun 1,2 , Zdenek Hodny 3 , Simona Moravcova 3 , Hana Hanzlikova 3 and Kamil Kuca 1,2,* 1 Department of Toxicology, Department of Public Health, Centre for Advanced Studies, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; 2 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; 3 Department of Genome Integrity, Institute of Molecular Genetics of the ASCR, v.v.i., Videnska 1083, 142 20 Prague, Czech Republic Abstract: Radiation and genotoxic drugs are two of the cornerstones of current cancer treatment strategy. However, this type of therapy often suffers from radio- or chemo-resistance caused by DNA repair mechanisms. With the aim of increasing the efficacy of these treatments, there has been great interest in studying DNA damage responses (DDR). Among the plethora of signal and effector proteins involved in DDR, three related kinases ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related) and DNA-PK (DNA-dependent protein kinase) play the main roles in initiation and regulation of signaling pathways in response to DNA double and single strand breaks (DSB and SSB). ATM inhibitors, as well as those of ATR and DNA-PK, provide an opportunity to sensitize cancer cells to therapy. Moreover, they can lead to selective killing of cancer cells, exploiting a concept known as synthetic lethality. However, only a very few selective inhibitors have been identified to this date. This mini-review is focused both on the development of selective inhibitors of ATM and other inhibitors which have ATM as one of their targets. Keywords: Ataxia telangiectasia mutated, cancer, chemosensitization, DNA damage response, phosphatidylinositol 3-kinase- related protein kinases, radiosensitization. INTRODUCTION The ataxia telangiectasia mutated (ATM) kinase is named from the rare multisystem disorder ataxia telangiectasia (A-T), which is caused by mutation in the ATM gene. This autosomal recessive disorder is characterized by various symptoms such as progressive cerebellar ataxia, telangiectasias, immunodeficiency, cancer predisposition and extreme radiation sensitivity. Cells with mutation in the ATM gene exhibit genomic instability, defective DNA damage-induced signaling pathways and cell cycle anomalies [1-4]. ATM is an atypical serine/threonine protein kinase and belongs to the phosphatidylinositol 3-kinase (PI3K)-related protein kinase (PIKK) family. Besides ATM, this family contains five other members: ataxia telangiectasia and Rad3- related (ATR), DNA-dependent protein kinase (DNA-PK), and human suppressor of morphogenesis in genitalia-1 (hSMG-1), which are all involved in DNA damage response (DDR); and mammalian target of rapamycin (mTOR), which plays a crucial role in regulation of cell proliferation and metabolism [5], and transformation/transcription associated protein (TRRAP), which is the only member devoid of kinase activity. All these proteins are large (ATM is 350 kDa protein with 3056 residues) and bear a kinase domain very similar to that of the PI3K family members [6, 7]. *Address correspondence to this author at the University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Tel: 00 420 495 832 923; E-mail: kamil.kuca@fnhk.cz ATM together with DNA-PK is a primary activator of the responses to double strand breaks (DSB), whereas ATR is activated by replication protein A (RPA)-coated single strand DNA [8]. The DSBs are probably the most lethal DNA lesions, and are caused by ionizing radiation (IR), certain chemotherapeutic drugs (e.g. topoisomerase inhibitors), reactive oxygen species (ROS), and by mechanical stress on the chromosomes [7, 9]. In non-irradiated cells, ATM kinase is held inactive as a dimer. The DSBs initiate rapid ATM autophosphorylation on Ser1981 and dimer dissociation, in cooperation with the MRE11-Rad50-NBS1 (MRN) complex, which acts as the main DSB sensor [1, 10, 11]. Dissociated and activated ATM passes the signal by phosphorylation of a broad range of downstream proteins triggering the complex and highly-branched signaling network (Fig. 1) [6, 12-14]. This network, in turn, activates both cell survival and cell death pathways, and the final outcome depends on a delicate balance between these opposing processes. Proper DNA repair is essential for maintaining genome stability and, in the case of DSBs, it occurs primarily by two distinct mechanisms: nonhomologous end-joining (NHEJ) and homologous recombination (HR) [15, 16]. ATM is an apical kinase, which is activated by various stimuli, including DSBs (the MRE-Rad50-NBS1 complex acts as a sensor), insulin, replication stress, chromatin modifications, hypoxia, hyperthermia and reactive oxygen species (ROS). In response to DSBs, ATM phosphorylates hundreds of proteins, represented in figure by p53, checkpoint kinase 2 (CHK2), breast and ovarian cancer-specific tumor 1875-5607/14 $58.00+.00 © 2014 Bentham Science Publishers