Discovery of novel ataxia telangiectasia mutated (ATM) kinase modulators: Computational simulation, biological evaluation and cancer combinational chemotherapy study

Discovery and Evaluation of 3-Quinoxalin Urea Derivatives as Potent, Selective, and Orally Available ATM Inhibitors Combined with Chemotherapy for the Treatment of Cancer via Goal-Oriented Molecule Generation and Virtual Screening

“…As the p-p53 (S15) induced by irinotecan was too low to be analyzed in this condition, the downstream phosphorylation level of p21 (T145) was applied to quantify the activation of p53/p21 signaling. 57 The co-treatment with AZ31 or 10r subsided irinotecaninduced p-ATM (S1981) and p-p21 (T145), and the degree of phosphorylation of p-ATM and p21 decreased with the increased concentration of 10r in particular. Subsequently, we further confirmed the expression of γH2AX via immunofluorescence in HCT116 cells, and representative microphotographs are shown in Figure 6F.…”

“…As shown in Figure A–E, irinotecan treatment did cause obvious DNA damage with significant upregulation of γH2AX, and it also activated the ATM signaling pathway in HCT116 cells such that the levels of phosphorylated ATM (S1981) and p21 (T145) were obviously upregulated, whereas the expression of total ATM protein was basically unchanged. As the p-p53 (S15) induced by irinotecan was too low to be analyzed in this condition, the downstream phosphorylation level of p21 (T145) was applied to quantify the activation of p53/p21 signaling . The co-treatment with AZ31 or 10r subsided irinotecan -induced p-ATM (S1981) and p-p21 (T145), and the degree of phosphorylation of p-ATM and p21 decreased with the increased concentration of 10r in particular.…”

“…Further, we performed molecular docking of these compounds based on the representative binding conformations of ATM proteins obtained by PCA and extracted the top 30 compounds scored for binding patterns. Finally, considering the predictive binding pattern analysis from known ATM inhibitors (Figure S7A), 57 ADMET property prediction, as well as our previous synthesis experience, molecule 7a was selected as the final screened lead compound after careful visual inspection (the predicted binding pattern of compound 7a is shown in Figure S7B). Initial Structure−Activity Relationship Exploration.…”

“…As shown in Figure 9A, 10r maintained primary key interactions similar to those in previous reports. 44,57 Concretely, the quinoxaline core acted as the monovalent hinge-binding motif, interacting with Cys2770 via a hydrogen bond to the quinoxaline nitrogen atom, and it also formed extensive π−π interactions toward the Trp2769 side chain of the hinge region. Because of the reduced volume of the binding pocket in the representative conformation (Figure S4), the pyridinyl N atom formed a hydrogen bond interaction with Asp2889 instead of the previously predicted interactions with Lys2717.…”

FTO-targeted siRNA delivery by MSC-derived exosomes synergistically alleviates dopaminergic neuronal death in Parkinson's disease via m6A-dependent regulation of ATM mRNA

“…The protein kinase ATM, known as a DNA repair protein, acts important roles in maintaining genome integrity [27]. Following damage-sensing Mre11, Rad50, and Nbs1 (MRN) complex in conjunction with DNA double-strand breaks, ATM is activated to phosphorylate numerous of substrates such as KAP1, Akt, and p53 to regulate diverse cellular processes, including DNA repair, cell apoptosis, and so on [34][35][36].In Huntington's disease, ATM is found to trigger mitochondrial-mediated apoptosis through activation of AMP-activated protein kinase (AMPK) [37]. Similarly, ATM is found to be specifically activated in the dopaminergic neurons to induce apoptosis in synucleinopathy models of PD [38,39].…”