Sandbox Reserved 1098: Difference between revisions

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Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.


The PAR protein is a potential target in drug discovery  as there are no close homologues of PARG[3]  .That’s why there has already been a lot of research concerning novel treatments.
The PAR protein is a potential target in drug discovery  as there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ[3]  .That’s why there has already been a lot of research concerning novel treatments.


As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.
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