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Thomas C , Ji Y , Lodhi N , Kotova E , Pinnola AD , Golovine K , Makhov P , Pechenkina K , Kolenko V , Tulin AV
Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo
EBioMedicine. 2016 Nov;13 :90-98
PMID: 27727003    PMCID: PMC5264309    URL: https://www.ncbi.nlm.nih.gov/pubmed/27727003
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The clinical potential of PARP-1 inhibitors has been recognized >10years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious problem for their clinical implementation. Present study aims to reignite clinical interest to PARP-1 inhibitors by introducing a new method of identifying highly potent inhibitors and presenting the largest known collection of structurally diverse inhibitors. The majority of PARP-1 inhibitors known to date have been developed as NAD competitors. NAD is utilized by many enzymes other than PARP-1, resulting in a trade-off trap between their specificity and efficacy. To circumvent this problem, we have developed a new strategy to blindly screen a small molecule library for PARP-1 inhibitors by targeting a highly specific rout of its activation. Based on this screen, we present a collection of PARP-1 inhibitors and provide their structural classification. In addition to compounds that show structural similarity to NAD or known PARP-1 inhibitors, the screen identified structurally new non-NAD-like inhibitors that block PARP-1 activity in cancer cells with greater efficacy and potency than classical PARP-1 inhibitors currently used in clinic. These non-NAD-like PARP-1 inhibitors are effective against several types of human cancer xenografts, including kidney, prostate, and breast tumors in vivo. Our pre-clinical testing of these inhibitors using laboratory animals has established a strong foundation for advancing the new inhibitors to clinical trials.
2352-3964 Thomas, Colin Ji, Yingbiao Lodhi, Niraj Kotova, Elena Pinnola, Aaron Dan Golovine, Konstantin Makhov, Peter Pechenkina, Kate Kolenko, Vladimir Tulin, Alexei V Journal article Netherlands EBioMedicine. 2016 Oct 4. pii: S2352-3964(16)30456-X. doi: 10.1016/j.ebiom.2016.10.001.