1.Nuclear magnetic resonance solution structures of inter- and intrastrand adducts of DNA cross-linker SJG-136.
Hopton SR1, Thompson AS. Biochemistry. 2011 May 31;50(21):4720-32. doi: 10.1021/bi102017e. Epub 2011 May 3.
SJG-136 (1) is a sequence-selective DNA-interactive agent that is about to enter phase II clinical trials for the treatment of malignant disease. Previous studies on the pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers, typified by SJG-136 and DSB-120 (2), have shown that these planar ligands react with the exocyclic NH(2) groups of two guanine bases in the base of the minor groove of DNA to form an irreversible interstrand cross-linked sequence-specific adduct. Using high-field NMR, we have characterized and modeled the previously predicted interstrand duplex adduct formed by SJG-136 with the self-complementary 5'-d(CICGATCICG)(2) duplex (4). This first SJG-136 NMR-refined adduct structure has been compared with previous high-field NMR studies of the adducts of the closely related PBD dimer DSB-120 with the same duplex and of the adduct of tomaymycin (3) formed with 5'-d(ATGCAT)(2). Surprisingly, the SJG-136 duplex adduct appears to be more closely related to the tomaymycin adduct than to the DSB-120 adduct with respect of the orientation and depth of insertion of the ligand within the minor groove.
2.γ-H2AX foci formation as a pharmacodynamic marker of DNA damage produced by DNA cross-linking agents: results from 2 phase I clinical trials of SJG-136 (SG2000).
Wu J1, Clingen PH, Spanswick VJ, Mellinas-Gomez M, Meyer T, Puzanov I, Jodrell D, Hochhauser D, Hartley JA. Clin Cancer Res. 2013 Feb 1;19(3):721-30. doi: 10.1158/1078-0432.CCR-12-2529. Epub 2012 Dec 18.
PURPOSE: To evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand cross-linking drugs.
3.Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours.
Mellinas-Gomez M1,2, Spanswick VJ3, Paredes-Moscosso SR4, Robson M5, Pedley RB6, Thurston DE7,8, Baines SJ9,10, Stell A11, Hartley JA12. BMC Vet Res. 2015 Aug 19;11:215. doi: 10.1186/s12917-015-0534-2.
BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies.