Pharma Strategy Blog

PARP's or POLY ADP-RIBOSE Polymerase Antibodies are a new generation of small molecules which may have potential applications in the treatment of cancer.

This class of agents was discovered almost 40 years ago by Pierre Chambon, J.D. Weill and Paul Mandel in Strasbourg with the synthesis of a yet uncharacterized polyadenylic acid upon addition of nicotinamide mononucleotide (NMN) in rat liver nuclear extracts.  In 1963 they published a paper entitled “Nicotinamide mononucleotide activation of a new DNA-dependent polyadenylic acid synthesizing enzyme” that launched the research on PARP metabolism.

By the early 1980's, the first evidence for the involvement of poly (ADP-ribosyl)ation in DNA repair was seen in the observation of the sensitization of cells to DNA damaging agents by 3-aminobenzamide, an efficient inhibitor of PARP.

Poly (ADP-ribose) polymerase (PARP) is essentially an abundant nuclear enzyme that mediates repair of DNA single strand breaks via the activation and recruitment of DNA repair enzymes.

PARP activation rescues tumor cells from therapeutic DNA damage induced by chemotherapy agents such as alkylating agents and topoisomerase I inhibitors.  PARP repairs alkylated bases by recruiting scaffolding proteins (XRCC1), DNA ligases (DNA ligase III), and polymerases (DNA pol beta), and mediates base excision repair (BER).

It is possible that PARP activation in this setting is a new basis for tumor resistance to chemotherapy. PARP inhibition, conversely, attenuates tumor resistance to alkylating agents and restores susceptibility of tumors to chemotherapy.

Recently, the biotechnology company Genentech signed a licensing deal with Inotek to develop their small molecule PARP, INO-1001.  INO-1001 represents the lead compound in a series of novel PARP inhibitors discovered by Inotek.  The agent is currently in Phase Ib testing for malignant melanoma in combination with temozolomide.

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{UPDATE:  sanofi-aventis and BiPar's PARP inhibitor, BSI-201, which is in phase II development will be presented at the ASCO Plenary session next month in triple negative breast cancer.  This is first time a PARP inhibitor has been covered in a major session there.}