BSI-401

DNA damages result from errors in replication, production of reactive oxygen species, and exposure to ultraviolet rays and ionizing radiation. These lesions that result from these noxious events include point mutations, single strand breaks (SSBs), double strand breaks (DSBs), intrastrand and interstrand cross-links. Cells employ multiple types of DNA repair mechanisms: base excision repair (BER), nucleic acid excision repair (NER), homologous recombination(HR), single strand annealing (SSA), Mismatch Repair (MMR), and nonhomologous end joining (NHEJ) to repair these damages on a regular basis. As a result of DNA repair, injured cells can survive, which is optimal for normal cells, but exactly the opposite of the goal for tumor cells that undergo DNA damage in response to chemotherapy or radiation. In addition, errors can occur in the repair process especially with NHEJ that can lead to new abnormalities and dysfunction of the cells. Certain genetic disorders, such as BRCA1 and BRCA2 mutations, as well as other genetic anomalies that prevent DNA repair are associated with increased risk of malignancies. [3] PARP is a family of proteins with enzymatic properties, scaffolding properties, and recruiting ability for other necessary DNA repair proteins. [4] PARP 1 and PARP 2 are the best known of these proteins and are critical for the function of BER. BER repairs single strand DNA breaks and inhibition of BER may ultimately lead to cell death. This makes PARP proteins ideal targets for anticancer therapy. PARP inhibitors interfere with BER and therefore DNA repair. By this route, PARP inhibitors can affect death of tumor cells. PARP inhibitors currently under clinical development are targeted to PARP 1 and PARP 2 proteins. They include Pfizer’s PF 01367338 (AG014699), AstraZeneca’s olaparib (AZD2281, KU-0059436), sanofi-aventis’ iniparib (BSI 201), Abbott Laboratories’ veliparib (ABT 888), Merck’s MK 4827, and Cephalon’s CEP 9722. Biomarin’s BMN673 (LT-673) and BiPar Science’s BSI 401 are in preclinical development.