Abstract #1921: Development of MK-4827: a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors

Poly(ADP-ribose) polymerase (PARP) -1 and -2 are key DNA-binding protein that are activated by DNA single-strand breaks and play a critical role in the base excision repair (BER) pathway. PARP inhibition as a therapeutic strategy in oncology is generating an increasing interest because of its potential to target pre-defined patient sub-populations with higher sensitivity and to widen the therapeutic index of chemotherapy and radiotherapy. In particular, it has been recently demonstrated that PARP inhibitors are synthetic lethal for tumors with defects in the homologous recombination (HR) pathway, such as tumors with mutations in the BRCA1 or BRCA2 genes. This presentation will focus on the development of MK-4827, a novel, potent and selective PARP-1/2 inhibitor that displays excellent activity in BRCA mutant cells with good selectivity over wild-type cells. This PARP inhibitor is orally bioavailable in preclinical species, and displays good pharmacokinetics. Animal models have been established to demonstrate that MK-4827 is strongly efficacious in mouse BRCA-deficient cancer models, while pharmacodynamic target engagement assays have been developed to monitor PARP inhibition in vivo and guide dose selection. MK-4827 has also been demonstrated to potentiate clinically-relevant chemotherapies in vitro and in xenograft models and to act as a radiosensitizer. The potential of MK-4827 for the therapy of tumors with defects in the HR pathway other than mutation in the BRCA genes will be discussed as well as possible strategies to identify HR-deficient tumors. Conclusion: MK-4827 is a novel, potent and highly selective PARP inhibitor which shows antitumor activity in different in vivo pre-clinical models: it is currently being evaluated in Phase I and has potential as a monotherapy agent for tumors with defects in the HR pathway and as a sensitizing agent in combination with cytotoxic agents and radiotherapy. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1921.