PNKP plays important roles
in both SSBR and DSBR repair, and
cancer cells depleted of PNKP are more sensitive to ionizing radiation and the Top I inhibitor camptothecin (85, 154-157), making PNKP a suitable target for inhibition (59, 100). Several reasons led to the choice of targeting the PNKP
phosphatase activity rather than the kinase. First, studies have indicated that
the phosphatase activity of PNKP takes precedence over the kinase activity (158, 159). Second, 3?-phosphate termini are produced more frequently
than 5?-OH by IR and ROS. Third, targeting the PNKP phosphatase (especially by
competitive inhibitors) is more specific than targeting the kinase activity.
Although the phosphatase belongs to the HAD superfamily, there are very few
enzymes with true similarity to mammalian PNKP (Dr. Mark Glover, personal
communication), while the kinase domain belongs to a superfamily with many
similar structures to the PNKP kinase (59, 100, 160).
Several members of a small
chemical library of imidopiperidine derivative compounds synthesized by Dr.
Dennis Hall’s group (Dept. of Chemistry, University of Alberta) were shown to
inhibit the phosphatase activity of PNKP (161, 162). A12B4C3, Figure 1.8,
was the first PNKP phosphatase inhibitor discovered in our lab. A12B4C3 is able to enhance the
radio/chemosensitivity of human A549 lung adenocarcinoma, MDA-MB-231 breast
carcinoma and acute myeloid leukemia cells (AML) (163-165). In addition, a
recent study showed that A12B4C3 can sensitize PC3 cells, which are
radioresistant, to high linear energy transfer (LET) radiation (166). Further kinetic analysis of A12B4C3 showed it to be a
non-competitive inhibitor (164).
This thesis discusses
attempts to optimize the lead compound A12B4C3 by identifying second generation
compounds that are more potent, and to design novel nanocarriers for targeted
delivery of the newly found inhibitors to cancer cells.