Ag014699

Good acceptor carbonyl group

Good acceptor carbonyl group

conformation

FIGURE 12.20 SAR conclusions for PARP inhibitors.

conformation

FIGURE 12.20 SAR conclusions for PARP inhibitors.

DNA damage (such as acute exposure to a large pathological insult), overactiva-tion of PARP results in cell-based energetic failure leading to cellular necrosis, tissue injury, and organ damage or failure. For this reason, some PARP inhibitors are being assayed for pathologies associated with damage caused by ROS, and INO-1001 has received orphan drug status from the Food and Drug Administration (FDA) to prevent post-surgical complications of aortic aneurysm repair.

3.3. Inhibitors of enzymes involved in double-strand DNA break repair pathways

Double strand breaks generated by ionizing radiation and ROS, or indirectly by DNA-damaging anticancer drugs such as alkylating agents and topoisomerase inhibitors, are repaired by either the HR or the NHEJ pathways. The enzymes involved in these pathways are members of the phosphatidylinositol 3-kinase (PI3K) superfamily and have become anticancer targets because their inhibition confers radio- or chemo-sensitization to tumor cells.85 These enzymes can be considered as molecular sensor of DSBs, and the most relevant targets in this area86 are

Ataxia telangiectasia mutated (ATM) kinase, which is involved in the HR pathway and plays a critical role in the maintenance of genome integrity by triggering DNA damage sensors through phosphorylation of downstream targets such as p53.87 DNA-dependant protein kinase (DNA-PK), which is involved in the NHEJ pathway.

The search for drugs that inhibit these pathways started from two non-selective PI-3 kinase inhibitors, namely wortmannin and LY-294002, that inhibit ATP binding within the catalytic site of the kinases. As shown in Fig. 12.21, the mechanism of inhibition by wortmannin relies on its reactivity as a Michael acceptor and involves the irreversible alkylation of a lysine unit that resides in the active site and is critical for the phosphate transfer (Lys-802 in the case of DNA-PK). Wortmannin is an effective radiosensitizer of a variety of normal and cancer cells, but its further development was hampered by its poor water solubility and its toxicity.

LY-294002 is another non-selective, competitive inhibitor of PI-3 kinases. Although this compound significantly sensitizers ATM-proficient cells to ionizing radiation and DBS-inducing chemotherapeutics, such as etoposide, doxorubicin, and camptothecin, its relatively low stability, fast metabolic degradation, and in vivo toxicity have prevented its clinical evaluation in humans. However, LY-294002 has been used as a lead compound in the development of further inhibitors. Thus, the ATM-selective inhibitor KU-55933 was discovered by screening a combinatorial library based around LY-294002,88 while the structurally related NU7026 demonstrated 70-fold more selectivity for DNA-PK compared to other PI-3 kinases and more than fivefold more selectivity with regard to ATM.

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