PNKP plays important rolesin both SSBR and DSBR repair, andcancer 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 PNKPphosphatase activity rather than the kinase. First, studies have indicated thatthe phosphatase activity of PNKP takes precedence over the kinase activity (158, 159). Second, 3?-phosphate termini are produced more frequentlythan 5?-OH by IR and ROS. Third, targeting the PNKP phosphatase (especially bycompetitive inhibitors) is more specific than targeting the kinase activity.Although the phosphatase belongs to the HAD superfamily, there are very fewenzymes with true similarity to mammalian PNKP (Dr.

Mark Glover, personalcommunication), while the kinase domain belongs to a superfamily with manysimilar structures to the PNKP kinase (59, 100, 160). Several members of a smallchemical library of imidopiperidine derivative compounds synthesized by Dr.Dennis Hall’s group (Dept. of Chemistry, University of Alberta) were shown toinhibit 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 theradio/chemosensitivity of human A549 lung adenocarcinoma, MDA-MB-231 breastcarcinoma and acute myeloid leukemia cells (AML) (163-165).

  In addition, arecent study showed that A12B4C3 can sensitize PC3 cells, which areradioresistant, to high linear energy transfer (LET) radiation (166). Further kinetic analysis of A12B4C3 showed it to be anon-competitive inhibitor (164). This thesis discussesattempts to optimize the lead compound A12B4C3 by identifying second generationcompounds that are more potent, and to design novel nanocarriers for targeteddelivery of the newly found inhibitors to cancer cells. 

Written by
admin
x

Hi!
I'm Colleen!

Would you like to get a custom essay? How about receiving a customized one?

Check it out