Science: Retouching anticancer drugs to get the best tumor cell killing effect

DOI: 10.1126/science.aax6367PARP inhibitors target PARP-1 enzymes, which are the primary responders to DNA structural fractures, a chronic genomic damage that requires continuous monitoring and repairPARP-1 has two main activities: binding to DNA fracture and forming a molecule called polysaccharidesPARP inhibitors are combined in the same region as PARP-1 to prevent PARP-1 from generating polyfusion (ADP-ribose), and this activity interferes with PARP-1's contribution to DNA damage repairIn healthy cells, the loss of PARP-1 contribution to DNA repair is acceptable, however, cancer cells with recombinant DNA repair mechanisms, such as those lacking the repair protein BRCA1 or BRCA2, have become dependent on PARP-1 and selectively killed by PARP inhibitorsPARP inhibitors have an effect on the conformation of PARP-1
the most effective in clinically effective PARP inhibitors tend to "capture" PARP-1 in DNA, which is thought to prevent cancer cell divisionThe researchers found that Veliparib, one of the PARP inhibitors, reduced the binding of PARP-1 to DNA compared to other inhibitors and was less effective in killing cancer cellsAs a result, Veliparib appears to combat the "capture" process of PARP-1 by reducing the interaction between PARP-1 and DNAThis result provides a key clue to the puzzle: by comparing the structure of Veliparib to clinical PARP inhibitors that capture PARP-1 on DNA, structural differences are identified, thus explaining the inhibitor's ability to capture or weaken its interaction with DNAresearchers used Veliparib as a starting molecule to design a new PARP inhibitor with the ability to increase PARP-1 interaction with DNA, with greater cancer cell lethality than Veli,' biochemical and structural studies were consistent and predictive in the behavior they observed in cell killing trialsconvert series III PARP inhibitors to type IPARP inhibitors have attracted great interest in the medical community and created new prospects for the treatment of diseasesThis study provides design principles for PARP inhibitors tailored to specific applications, and understanding the structure and biochemical methods of PARP-1 can guide the continued development of PARP inhibitorsIn addition to being used in cancer treatment, the use of PARP inhibitors is also being evaluated in other indications such as cardiovascular disease and inflammationReferences:s S S S S S S S S S S Rei on DNA s Tailoring an anti-cancer drug for optimal tumor cell cell killing original title: Science: Tailored anti-cancer drugs for best tumor cell killing