SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer pro-drug that cross-links DNA and exerts highly potent antitumor activity

Abstract

The pyrrolobenzodiazepines (PBDs) are naturally occurring antitumor antibiotics and a PBD dimer (SJG-136, SG2000) is in Phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. The novel compound SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble pro-drug of SG2202 in which two bisulphite groups inactivate the PBD N10-C11 imines. Once the bisulphites are eliminated, the imine moieties can bind covalently in the DNA minor groove forming an interstrand cross-link. The mean in vitro cytotoxic potency of SG2285 against human tumour cell lines is GI50 20 pM. SG2285 is highly efficient at producing DNA interstrand cross-links in cells, but they form more slowly than those produced by SG2202. Cellular sensitivity to SG2285 was dependent primarily on ERCC1 and homologous recombination repair. In primary B-CLL samples the mean LD50 was significantly lower than in normal age-matched B- and T-lymphocytes. Antitumor activity was demonstrated in several human tumor xenograft models, including ovarian, non-small cell lung, prostate, pancreatic and melanoma, with cures obtained in the latter model with a single dose. Further, in an advanced stage colon model, SG2285 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. Our findings define SG2285 as a highly active cytotoxic compound with antitumor properties desirable for further development.