Current Overview on the Usage of Poly(ADP-ribose)polymerase (PARP) Inhibitors in Treating Cancer
Clinical Cancer Drugs, 1
): 127-148.Author(s): Manikanta Swamy Murahari
and Mayur C Yergeri
Department of Pharmaceutical Chemistry, Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai-400056, India.
AbstractRecent studies have shown that certain genetically modified tumour cells are extremely sensitive to the effects of PARP-1 inhibition without the need for the presence of a cytotoxic agent leading to selective cell death. For example BRCA1 and BRCA2, which are components of the homologous recombination DNA repair pathway, are deleted in 5- 10% breast cancer patients and have showed that PARP-1 inhibitors are highly effective agents as monotherapy. These results indicate that for cancer treatment, the PARP inhibitors, whether as individual agents or in combination with chemotherapeutics or as potential monotherapies, could be of significant therapeutic importance. Previous investigators have designed inhibitors of PARP-1 to mimic the substrate-protein interactions of NAD+ with the enzyme. Mechanistically, these compounds inhibit PARP-1 by blocking and binding to the substrate, particularly the nicotinamide moiety, to the active site of the enzyme. Early weak inhibitors such as 3-aminobenzamide have been developed into more potent PARP-1 inhibitors derived from a range of related pharmacophoric templates. Further lead optimisation focussed primarily on enhancement of pharmacokinetic properties has afforded orally available PARP-1 inhibitors for use either in combination or with existing cytotoxics or as a monotherapy in target tumour types. The current review gives an idea about the role and applications of PARP in cancer therapy. This review discusses molecular modelling strategies and synthetic applications so far reported. The author also discusses how SAR can yield new PARP inhibitors with lesser side effects.
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