ATM and ATR cooperate to mediate cellular responses to DNA damage, following exposure to diverse genotoxic agents. These include induction of cell cycle arrest, DNA repair, maintenance of genomic stability, induction of premature senescence and cell death [
1‐
3]. The coordinated activation of these processes has been defined as the DNA damage response pathway (DDR). Initial studies demonstrated that inhibition of ATM and ATR by caffeine significantly enhanced cellular sensitivity to ionizing radiation (IR) [
4]. Inhibiting ATM, ATR or their downstream targets thus serves to widen the therapeutic window of genotoxic anti-cancer therapeutics by sensitizing cancer cells to these agents (reviewed [
5]). The relative non-specificity of caffeine has lead to the search for more specific inhibitors of ATM and ATR. The small molecule inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (KU55933) has been shown to specifically inhibit ATM in the low nanomolar range (IC
50:12.9 nM). In contrast, KU55933 did not inhibit ATR at doses of up to 100 μM [
6]. KU55933 has been shown to sensitize cancer cells to both IR and chemotherapeutic agents [
6,
7]. CGK733, a thiourea-containing compound, was originally identified as an inhibitor of ATM and ATR with an IC
50 of ~200 nM towards both kinases [
8]. This study was subsequently retracted, leaving the precise molecular pharmacology of this compound unclear. Additional studies suggest however, that CGK733 inhibits ATM and ATR [
9‐
12]. More recently, caffeine, CGK733 and KU55933 have been shown to induce cell death in prematurely senescent breast cancer cells [
13]. The induction of premature senescence by genotoxic agents contributes to drug sensitivity and is primarily (but not solely) dependent on p53-induced p21 expression [
14,
15]. Cancer cells that have undergone drug-induced premature senescence are less sensitive to pro-apoptotic signaling and can re-enter the cell cycle [
16‐
20]. The study by Crescenzi
et al. [
13] suggests that ATM is required for the maintenance of the premature senescent phenotype and hence the survival of cancer cells exposed to genotoxins. Combining ATM and/or ATR inhibitors with genotoxins may thus further enhance the cytotoxicity of these agents, by preventing drug induced senescence as a therapeutic outcome [
13]. The molecular pharmacology of inhibitors like CGK733 and KU55933 will require further characterization. ATR unlike ATM regulates cell cycle progression in the absence of DNA damage and is required for the viability of proliferating human and mouse cells [
1]. Inhibitors that target both ATM and ATR are thus likely to exhibit pharmacological profiles that are distinct from ATM selective inhibitors. It is also likely, that the genetic make up of a particular subset of cancer cells influences their relative sensitivity to ATM and/or ATR inhibitors [
21,
22].