DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine dimer SG2057

Abstract

The pyrrolobenzodiazepines (PBDs) are naturally occurring antitumor antibiotics and a PBD dimer (SJG-136, SG2000) is in Phase II trials. SG2000 is a propyldioxy linked PBD dimer which binds sequence selectively in the minor groove of DNA forming DNA interstrand and intrastrand cross-linked adducts, and also mono-adducts depending on sequence. SG2057 is the corresponding dimer containing a pentyldioxy linkage. SG2057 has multilog differential in vitro cytotoxicity against a panel of human tumour cell lines with a mean GI(50) of 212 pM. The agent is highly efficient at producing DNA interstrand cross-links in cells which form rapidly and persist over a 48 h period. Significant antitumor activity was demonstrated in several human tumor xenograft models. Cures were obtained in a LOX-IMVI melanoma model following a single administration and dose-dependent activity, including regression responses, observed in SKOV-3 ovarian and HL-60 promyelocytic leukemia models following repeat dose schedules. In the advanced stage LS174T model, SG2057 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. SG2057 is therefore a highly active antitumor agent, with more potent in vitro activity and superior in vivo activity to SG2000, warranting further development.

From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs)

“…[67] SJG-136 was initially evaluated in eight different cell lines using the MTT growth inhibition assay, and an average GI 50 (concentration for 50 % maximal inhibition of cell proliferation) of 212 pm was determined (range: 2.1 pm in ovarian A2780 to 2.3 nm in colon HCT-15). [67] The Comet assay was then used to detect DNA interstrand cross-links in some of these cell lines following a one hour exposure to SJG-136 at 0.1 nm to 10 mm. The Comet assay involves exposure of cells to X-rays which cause the nuclear DNA to fragment and electrophorese with a long (i.e., Comet-like) tail.…”

Antibody‐Drug Conjugates for the Treatment of Cancer

“…These payloads have in common exquisite potency often in the picomolar range across a variety of human tumor cell lines. Dimerizing two PBD units together allows the resulting compound to cross-link DNA via the N2 of guanine on opposing strands of DNA (58). Pyrrolobenzodiazepines (PBDs) are a class of naturally occurring antitumor antibiotics that bind in a sequence specific manner in the minor groove of DNA (57).…”

“…Pyrrolobenzodiazepines (PBDs) are a class of naturally occurring antitumor antibiotics that bind in a sequence specific manner in the minor groove of DNA (57). Dimerizing two PBD units together allows the resulting compound to cross-link DNA via the N2 of guanine on opposing strands of DNA (58). The PBD dimers have picomolar activity against many human tumor cell lines.…”

Entwicklung Pyrrolobenzodiazepin(PBD)‐haltiger Antikörper‐Wirkstoff‐Konjugate (ADCs) ausgehend von Anthramycin

“…[67] SJG-136 wurde zunächst in acht verschiedenen Zelllinien mit dem MTTWachstumsinhibierungstest untersucht, und ein durchschnittlicher GI 50 -Wert (die Konzentration, bei der 50 % der maximalen Inhibierung der Zellproliferation auftritt) von 212 pm wurde bestimmt (Bereich: 2.1 pm in ovarialen A2780-Zellen bis 2.3 nm in Darm-HCT-15-Zellen). [67] Der CometAssay wurde in einigen dieser Zelllinien zur Erkennung von Vernetzungen zwischen DNA-Strängen nach einer einstün-digen Behandlung mit SJG-136 bei 0.1 nm bis 10 mm eingesetzt. Der Comet-Assay umfasst die Bestrahlung von Zellen mit Rçntgenstrahlen, wodurch die nukleare DNA fragmentiert und bei der Elektrophorese eine langgezogene Spur (d. h. ähnlich wie ein Komet) liefert.…”