SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug with potent antitumor activity

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3302 The pyrrolobenzodiazepines (PBDs) are a family of naturally occurring antitumor antibiotics. Many of the most potent family members contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring of the PBD. SG2202 is a PBD dimer consisting of two PBD monomer units, which retain the endo-exo unsaturation motif in the form of a C2-aryl substituent conjugated to a 2,3 double bond, joined via their C8/C8’ positions through a propyldioxy linker. SG2285 is a prodrug of SG2202 whereby two bisulphite groups inactivate the N10-C11 imines of the PBD units. Once the bisulphite groups are eliminated to produce SG2202 the two PBD imine moieties are able to bind covalently in the minor groove of DNA to the N2-positions of guanine on opposite strands of DNA to form an interstrand crosslink (ICL). SG2285 is highly potent in vitro, with sub-nM GI50 values in most human tumour cell lines tested using the Alamar blue assay following continuous exposure. A modification of the single cell gel electrophoresis (comet) assay has shown SG2285 to be highly efficient at producing ICLs in cells, which form more slowly than those produced by SG2202. Using DNA repair-deficient cell lines cellular sensitivity to SG2285 was shown to be dependent on the ERCC1/XPF heterodimer and homologous recombination. In 20 primary chronic lymphocytic leukaemia (B-CLL) samples the mean LD50 value (Annexin V / propidium iodide assay) was 8.3(±3.4) nM. Although there was a trend towards increased resistance to SG2285 in cells from previously treated (n=10) compared to untreated (n=10) patients this did not reach significance (p=0.07). LD50 values in normal age-matched B- and T-lymphocytes were significantly higher (p<0.0001). DNA ICLs were detectable at 12 hours increasing to 48 hours in B-CLL cells following treatment with 2nM SG2285. In vivo antitumor activity has been demonstrated in all six human tumor xenograft models tested. Cures were obtained in early-stage LOX melanoma following a single administration at one fifth of the MTD. SG2285 also produced significant growth delays in colon HT-29, ovarian OVCAR-5 and melanoma C32 models following a single dose. In an advanced stage (mean tumor volume 300 mm3) LS174T colon model it was highly active and superior to irinotecan when administered either as a single dose, qdx5 or q4dx3. Significant activity was also seen using the same schedules in the SKOV3 ovarian model. Based on these data, SG2285 is currently in pre-clinical development in preparation for Phase I clinical trial.