title: SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug that cross-links DNA and exerts highly potent antitumor activity.
abstract: The pyrrolobenzodiazepines (PBD) 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 prodrug of SG2202 in which two bisulfite groups inactivate the PBD N10-C11 imines. Once the bisulfites 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 tumor cell lines is GI(50) 20 pmol/L. 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 primarily dependent on ERCC1 and homologous recombination repair. In primary B-cell chronic lymphocytic leukemia samples, the mean LD(50) was significantly lower than in normal age-matched B and T lymphocytes. Antitumor activity was shown 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.
authors.affiliation: Spirogen Ltd., UCL Cancer Institute, UK. john.hartley@ucl.ac.uk.
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Anzu
authors.initials: A
authors.lastname: Hamaguchi
authors.forename: Marissa
authors.initials: M
authors.lastname: Coffils
authors.forename: Christopher R H
authors.initials: CR
authors.lastname: Martin
authors.forename: Marie
authors.initials: M
authors.lastname: Suggitt
authors.forename: Zhizhi
authors.initials: Z
authors.lastname: Chen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gregson
authors.forename: Luke A
authors.initials: LA
authors.lastname: Masterson
authors.forename: Arnaud C
authors.initials: AC
authors.lastname: Tiberghien
authors.forename: Janet M
authors.initials: JM
authors.lastname: Hartley
authors.forename: Christopher
authors.initials: C
authors.lastname: Pepper
authors.forename: Thet Thet
authors.initials: TT
authors.lastname: Lin
authors.forename: Christopher
authors.initials: C
authors.lastname: Fegan
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D011355:Prodrugs / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D001570:Benzodiazepinones; D011355:Prodrugs; D011758:Pyrroles; C552531:SG 2285