Pyrrolobenzodiazepine (SJG-136, NSC 694501)

1997 Pyrrolobenzodiazepine (SJG-136, NSC 694501) is a synthetic dimer based on the naturally occurring anthramycin family of antitumor antibiotics. SJG-136 is a highly efficient cross-linking agent of naked DNA.¹ Study results suggest that it has a unique mechanism of action compared with other DNA-binding agents.^2,3 Based on high potency in the NCI human tumor cell line in vitro screen, the compound was tested in the DTP hollow fiber assay, in which it achieved one of the highest scores ever recorded against a panel of 12 tumor types. The agent was then evaluated against numerous solid tumor models. Tumor-free animals were reported in several of the models, including subcutaneous implanted SF-295 (brain) tumors.

1999 In 1999, based on positive activity against several solid tumors in animals, SJG-136 was selected as a candidate for clinical development.

2003 Acceptable results of pharmacokinetic and toxicology studies led to the filing of an IND for SJG-136. The compound is currently in phase I clinical trials in the United States and in the United Kingdom.

¹ Gregson SJ, Howard PW, Hartley JA, Brooks NA, Adams LJ, Jenkins TC, Kelland LR, Thurston DE. Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity. J Med Chem 2001;44:737–748.

² Hartley JA, Spanswick VJ, Brooks N, Clingen PH, McHugh PJ, Hochhauser D, Pedley RB, Kelland LR, Alley MC, Schultz R, Hollingshead MG, Schweikart KM, Tomaszewski JE, Sausville EA, Gregson SJ, Howard PW, Thurston DE. SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity. Cancer Res 2004;64:6693–6699.

³ Alley MC, Hollingshead MG, Pacula-Cox CM, Waud WR, Hartley JA, Howard PW, Gregson SJ, Thurston DE, Sausville EA. SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 2: efficacy evaluations. Cancer Res 2004;64:6700–6706.

Link:

DTP SJG-136 poster (pdf)

“Preliminary evidence suggests that, unlike many other DNA-interactive agents, SJG-136-induced cytotoxicity is independent of p53 activation. Given that mutation and aberrant expression of the p53 tumor are the most frequent molecular alterations in human malignancy and contribute to genomic instability, carcinogenesis, and treatment failure, this feature of SJG-136 many prove to be one of its most interesting attributes.” Cancer Research, September 15, 2004.