In Vitro

BSI-201 is described as a prodrug of 4-iodo-3-nitrosobenzamide, an agent that covalently inhibits PARP1 by binding to its first zinc finger under cell-free conditions. Treatment of 120 μM BSI-201 plus buthionine sulfoximine (BSO) induces a 95% cell death among 855-2 cells, and displays a similar effect in other human cancer cells. ^[1] BSI-201 inhibits the growth of E-ras 20 cells, the effect of which can be augmented 4-fold when BOS is added. ^[2] Recently BSI-201 shows no ability to inhibit PARP enzymatic or cellular activity, but can non-selectively modify cysteine-containing proteins in tumor cells, suggesting the mechanism of action for BSI-201 is likely not via inhibition of PARP activity. ^[3] BSI-201 (100 μM) inhibits ionizing radiation-induced single-strand breaks (SSBs) repair in human lymphoid cell lines based on large endogenous Epstein–Barr virus (EBV) circular episomes assay, resulting in 55% repair by 2 hours, which can be reversed surprisingly by knockdown of PARP1, indicating that the mechanism of inhibition does not involve trapping PARP at SSBs. ^[4] BSI-201 is not able to selectively kill homologous recombination (HR)-deficient cells between BRCA2-deficient PEO1 and BRCA2-revertant PEO4, or ATM-deficient GM16666 and ATM-restored GM16667 fibroblasts. Although able to modestly sensitize cells to etoposide, BSI-201 fails to sensitize SKOV3 cells to topoisomerase I poisons, cisplatin, gemcitabine, or paclitaxel, or inhibit pADPr formation in situ at concentrations up to 100 μM. In contrast, BSI-201 is cytotoxic to a variety of cell lines at concentrations above 40 μM reflecting a mechanism independent of PARP. ^[5]

In Vivo

Clinical Trials

Features