PARP inhibitors.

Maheen Anwar,Shahzad Anwar,Hafiz Muhammad Aslam

doi:10.1186/s13053-014-0024-8

PARP inhibitors.

Maheen Anwar, Shahzad Anwar + Show 1 more

Open Access

https://doi.org/10.1186/s13053-014-0024-8

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Abstract

Poly (ADP-ribose) polymerases, abbreviated as PARPs, are a group of familiar proteins that play a central role in DNA repair employing the base excision repair (BER) pathway. There about 17 proteins in this family out of which the primary nuclear PARPs are PARP-1, PARP-2, PARP-3, and tankyrases 1 and 2 (PARP-5a and -5b) .The PARP family members are known to engage in a wide range of cellular activities, for example, DNA repair, transcription, cellular signaling, cell cycle regulation and mitosis amongst others. The chief functional units of PARP-1 are an amino terminal DNA binding domain (DBD), a central auto modification domain (AMD), and a carboxyl-terminal catalytic domain (CD). PARP inhibitors are currently undergoing clinical trials as targeted treatment modalities of breast, uterine, colorectal and ovarian cancer. This review summarizes current insights into the mechanism of action of PARP inhibitors, its recent clinical trials, and potential next steps in the evaluation of this promising class of anti-cancer drugs.

Highlights

Environmental exposures and cell replication result in DNA damage that is repaired by a variety of mechanisms, including base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), single strand annealing (SSA), homologous recombination (HR), and
poly(ADP-ribose) polymerase (PARP) inhibitors in clinical development imitate the nicotinamide moiety of nicotinamide adenine dinucleotide, and bind to the enzyme’s catalytic domain, inhibiting auto modification and subsequent release of the enzyme from the site of DNA damage
PARP inhibitors were recently developed on the rationale of synthetic lethality, this concept was well illustrated by Byrant et all and Farmer et all in 2005. They demonstrated that, breast cancer cells containing germ line mutations in BRCA1 and BRCA 2 genes become sensitized to PARP inhibitors in a PARP1 dependant manner and lose sensitivity to PARP inhibition on regaining BRCA2 functionality [19]

Summary

Introduction

PARP inhibitors in clinical development imitate the nicotinamide moiety of nicotinamide adenine dinucleotide, and bind to the enzyme’s catalytic domain, inhibiting auto modification and subsequent release of the enzyme from the site of DNA damage. PARP inhibitors are currently undergoing clinical trials as targeted treatment modalities for cancer. Clinical trials have been undertaken to assess the safety and efficacy profiles of PARP inhibitors for management of breast, uterine, colorectal and ovarian cancers [1].

Results

Conclusion