SG2285, a Novel C2-Aryl-Substituted Pyrrolobenzodiazepine Dimer Prodrug That Cross-links DNA and Exerts Highly Potent Antitumor Activity

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 17; pp. 6849 - 6858
• Main Authors: HARTLEY, John A, HAMAGUCHI, Anzu, PEPPER, Christopher, THET THET LIN, FEGAN, Christopher, THURSTON, David E, HOWARD, Philip W, COFFILS, Marissa, MARTIN, Christopher R. H, SUGGITT, Marie, ZHIZHI CHEN, GREGSON, Stephen J, MASTERSON, Luke A, TIBERGHIEN, Arnaud C, HARTLEY, Janet M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2010
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Benzodiazepinones - pharmacology; Biological and medical sciences; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Female; Humans; Medical sciences; Mice; Neoplasms - drug therapy; Pharmacology. Drug treatments; Prodrugs - pharmacology; Pyrroles - pharmacology; Tumors; Xenograft Model Antitumor Assays; Antineoplastic agent; Crosslinking; Dimer; Prodrug; DNA; Biological activity
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-0790

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.